Nucleic acid and corresponding protein entitled 98P4B6 useful in treatment and detection of cancer

ABSTRACT

A novel gene 098P4B6 (also designated STEAP-2) and its encoded protein, and variants thereof, are described wherein 98P4B6 exhibits tissue specific expression in normal adult tissue, and is aberrantly expressed in the cancers listed in Table I. Consequently, 98P4B6 provides a diagnostic, prognostic, prophylactic and/or therapeutic target for cancer. The 98P4B6 gene or fragment thereof, or its encoded protein, or variants thereof, or a fragment thereof, can be used to elicit a humoral or cellular immune response; antibodies or T cells reactive with 98P4B6 can be used in active or passive immunization.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/407,484, filed Apr. 4, 2003, which is a continuation-in-part of U.S.patent application Ser. No. 09/455,486, filed Dec. 6, 1999, now issuedas U.S. Pat. No. 6,833,438 on Dec. 21, 2004, which is acontinuation-in-part of U.S. patent application Ser. No. 09/323,873,filed Jun. 1, 1999, now issued as U.S. Pat. No. 6,329,503 on Dec. 11,2001, which claims the benefit of U.S. Provisional Application No.60/091,183, filed Jun. 30, 1998 and U.S. Provisional Application No.60/087,520, filed Jun. 1, 1998. This application relates to U.S.Provisional Application No. 60/370,387, filed Apr. 5, 2002, U.S.Provisional Application No. 60/435,480, filed Dec. 20, 2002, U.S. patentapplication Ser. No. 10/455,822, filed Jun. 4, 2003, U.S. patentapplication Ser. No. 10/862,182, filed Jun. 4, 2004, now abandoned, U.S.application Ser. No. 11/068,859, filed Feb. 28, 2005, U.S. ProvisionalApplication No. 60/296,656, filed Jun. 6, 2001, U.S. patent applicationSer. No. 10/165,044, filed Jun. 6, 2002, and U.S. patent applicationSer. No. 10/753,195, filed Jan. 6, 2004. The contents of theapplications listed in this paragraph are fully incorporated byreference herein.

STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH

Not applicable.

FIELD OF THE INVENTION

The invention described herein relates to genes and their encodedproteins, termed 98P4B6 or STEAP-2, expressed in certain cancers, and todiagnostic and therapeutic methods and compositions useful in themanagement of cancers that express 98P4B6.

BACKGROUND OF THE INVENTION

Cancer is the second leading cause of human death next to coronarydisease. Worldwide, millions of people die from cancer every year. Inthe United States alone, as reported by the American Cancer Society,cancer causes the death of well over a half-million people annually,with over 1.2 million new cases diagnosed per year. While deaths fromheart disease have been declining significantly, those resulting fromcancer generally are on the rise. In the early part of the next century,cancer is predicted to become the leading cause of death.

Worldwide, several cancers stand out as the leading killers. Inparticular, carcinomas of the lung, prostate, breast, colon, pancreas,and ovary represent the primary causes of cancer death. These andvirtually all other carcinomas share a common lethal feature. With veryfew exceptions, metastatic disease from a carcinoma is fatal. Moreover,even for those cancer patients who initially survive their primarycancers, common experience has shown that their lives are dramaticallyaltered. Many cancer patients experience strong anxieties driven by theawareness of the potential for recurrence or treatment failure. Manycancer patients experience physical debilitations following treatment.Furthermore, many cancer patients experience a recurrence.

Worldwide, prostate cancer is the fourth most prevalent cancer in men.In North America and Northern Europe, it is by far the most commoncancer in males and is the second leading cause of cancer death in men.In the United States alone, well over 30,000 men die annually of thisdisease—second only to lung cancer. Despite the magnitude of thesefigures, there is still no effective treatment for metastatic prostatecancer. Surgical prostatectomy, radiation therapy, hormone ablationtherapy, surgical castration and chemotherapy continue to be the maintreatment modalities. Unfortunately, these treatments are ineffectivefor many and are often associated with undesirable consequences.

On the diagnostic front, the lack of a prostate tumor marker that canaccurately detect early-stage, localized tumors remains a significantlimitation in the diagnosis and management of this disease. Although theserum prostate specific antigen (PSA) assay has been a very useful tool,however its specificity and general utility is widely regarded aslacking in several important respects.

Progress in identifying additional specific markers for prostate cancerhas been improved by the generation of prostate cancer xenografts thatcan recapitulate different stages of the disease in mice. The LAPC (LosAngeles Prostate Cancer) xenografts are prostate cancer xenografts thathave survived passage in severe combined immune deficient (SCID) miceand have exhibited the capacity to mimic the transition from androgendependence to androgen independence (Klein et al., 1997, Nat. Med.3:402). More recently identified prostate cancer markers include PCTA-1(Su et al., 1996, Proc. Natl. Acad. Sci. USA 93: 7252),prostate-specific membrane (PSM) antigen (Pinto et al., Clin Cancer Res1996 Sep. 2 (9): 1445-51), STEAP (Hubert, et al., Proc Natl Acad SciUSA. 1999 Dec. 7; 96(25): 14523-8) and prostate stem cell antigen (PSCA)(Reiter et al., 1998, Proc. Natl. Acad. Sci. USA 95: 1735).

While previously identified markers such as PSA, PSM, PCTA and PSCA havefacilitated efforts to diagnose and treat prostate cancer, there is needfor the identification of additional markers and therapeutic targets forprostate and related cancers in order to further improve diagnosis andtherapy.

Renal cell carcinoma (RCC) accounts for approximately 3 percent of adultmalignancies. Once adenomas reach a diameter of 2 to 3 cm, malignantpotential exists. In the adult, the two principal malignant renal tumorsare renal cell adenocarcinoma and transitional cell carcinoma of therenal pelvis or ureter. The incidence of renal cell adenocarcinoma isestimated at more than 29,000 cases in the United States, and more than11,600 patients died of this disease in 1998. Transitional cellcarcinoma is less frequent, with an incidence of approximately 500 casesper year in the United States.

Surgery has been the primary therapy for renal cell adenocarcinoma formany decades. Until recently, metastatic disease has been refractory toany systemic therapy. With recent developments in systemic therapies,particularly immunotherapies, metastatic renal cell carcinoma may beapproached aggressively in appropriate patients with a possibility ofdurable responses. Nevertheless, there is a remaining need for effectivetherapies for these patients.

Of all new cases of cancer in the United States, bladder cancerrepresents approximately 5 percent in men (fifth most common neoplasm)and 3 percent in women (eighth most common neoplasm). The incidence isincreasing slowly, concurrent with an increasing older population. In1998, there was an estimated 54,500 cases, including 39,500 in men and15,000 in women. The age-adjusted incidence in the United States is 32per 100,000 for men and eight per 100,000 in women. The historicmale/female ratio of 3:1 may be decreasing related to smoking patternsin women. There were an estimated 11,000 deaths from bladder cancer in1998 (7,800 in men and 3,900 in women). Bladder cancer incidence andmortality strongly increase with age and will be an increasing problemas the population becomes more elderly.

Most bladder cancers recur in the bladder. Bladder cancer is managedwith a combination of transurethral resection of the bladder (TUR) andintravesical chemotherapy or immunotherapy. The multifocal and recurrentnature of bladder cancer points out the limitations of TUR. Mostmuscle-invasive cancers are not cured by TUR alone. Radical cystectomyand urinary diversion is the most effective means to eliminate thecancer but carry an undeniable impact on urinary and sexual function.There continues to be a significant need for treatment modalities thatare beneficial for bladder cancer patients.

An estimated 130,200 cases of colorectal cancer occurred in 2000 in theUnited States, including 93,800 cases of colon cancer and 36,400 ofrectal cancer. Colorectal cancers are the third most common cancers inmen and women. Incidence rates declined significantly during 1992-1996(−2.1% per year). Research suggests that these declines have been due toincreased screening and polyp removal, preventing progression of polypsto invasive cancers. There were an estimated 56,300 deaths (47,700 fromcolon cancer, 8,600 from rectal cancer) in 2000, accounting for about11% of all U.S. cancer deaths.

At present, surgery is the most common form of therapy for colorectalcancer, and for cancers that have not spread, it is frequently curative.Chemotherapy, or chemotherapy plus radiation, is given before or aftersurgery to most patients whose cancer has deeply perforated the bowelwall or has spread to the lymph nodes. A permanent colostomy (creationof an abdominal opening for elimination of body wastes) is occasionallyneeded for colon cancer and is infrequently required for rectal cancer.There continues to be a need for effective diagnostic and treatmentmodalities for colorectal cancer.

There were an estimated 164,100 new cases of lung and bronchial cancerin 2000, accounting for 14% of all U.S. cancer diagnoses. The incidencerate of lung and bronchial cancer is declining significantly in men,from a high of 86.5 per 100,000 in 1984 to 70.0 in 1996. In the 1990s,the rate of increase among women began to slow. In 1996, the incidencerate in women was 42.3 per 100,000.

Lung and bronchial cancer caused an estimated 156,900 deaths in 2000,accounting for 28% of all cancer deaths. During 1992-1996, mortalityfrom lung cancer declined significantly among men (−1.7% per year) whilerates for women were still significantly increasing (0.9% per year).Since 1987, more women have died each year of lung cancer than breastcancer, which, for over 40 years, was the major cause of cancer death inwomen. Decreasing lung cancer incidence and mortality rates most likelyresulted from decreased smoking rates over the previous 30 years;however, decreasing smoking patterns among women lag behind those ofmen. Of concern, although the declines in adult tobacco use have slowed,tobacco use in youth is increasing again.

Treatment options for lung and bronchial cancer are determined by thetype and stage of the cancer and include surgery, radiation therapy, andchemotherapy. For many localized cancers, surgery is usually thetreatment of choice. Because the disease has usually spread by the timeit is discovered, radiation therapy and chemotherapy are often needed incombination with surgery. Chemotherapy alone or combined with radiationis the treatment of choice for small cell lung cancer; on this regimen,a large percentage of patients experience remission, which in some casesis long lasting. There is however, an ongoing need for effectivetreatment and diagnostic approaches for lung and bronchial cancers.

An estimated 182,800 new invasive cases of breast cancer were expectedto occur among women in the United States during 2000. Additionally,about 1,400 new cases of breast cancer were expected to be diagnosed inmen in 2000. After increasing about 4% per year in the 1980s, breastcancer incidence rates in women have leveled off in the 1990s to about110.6 cases per 100,000.

In the U.S. alone, there were an estimated 41,200 deaths (40,800 women,400 men) in 2000 due to breast cancer. Breast cancer ranks second amongcancer deaths in women. According to the most recent data, mortalityrates declined significantly during 1992-1996 with the largest decreasesin younger women, both white and black. These decreases were probablythe result of earlier detection and improved treatment.

Taking into account the medical circumstances and the patient'spreferences, treatment of breast cancer may involve lumpectomy (localremoval of the tumor) and removal of the lymph nodes under the arm;mastectomy (surgical removal of the breast) and removal of the lymphnodes under the arm; radiation therapy; chemotherapy; or hormonetherapy. Often, two or more methods are used in combination. Numerousstudies have shown that, for early stage disease, long-term survivalrates after lumpectomy plus radiotherapy are similar to survival ratesafter modified radical mastectomy. Significant advances inreconstruction techniques provide several options for breastreconstruction after mastectomy: Recently, such reconstruction has beendone at the same time as the mastectomy.

Local excision of ductal carcinoma in situ (DCIS) with adequate amountsof surrounding normal breast tissue may prevent the local recurrence ofthe DCIS. Radiation to the breast and/or tamoxifen may reduce the chanceof DCIS occurring in the remaining breast tissue. This is importantbecause DCIS, if left untreated, may develop into invasive breastcancer. Nevertheless, there are serious side effects or sequelae tothese treatments. There is, therefore, a need for efficacious breastcancer treatments.

There were an estimated 23,100 new cases of ovarian cancer in the UnitedStates in 2000. It accounts for 4% of all cancers among women and rankssecond among gynecologic cancers. During 1992-1996, ovarian cancerincidence rates were significantly declining. Consequent to ovariancancer, there were an estimated 14,000 deaths in 2000. Ovarian cancercauses more deaths than any other cancer of the female reproductivesystem.

Surgery, radiation therapy, and chemotherapy are treatment options forovarian cancer. Surgery usually includes the removal of one or bothovaries, the fallopian tubes (salpingo-oophorectomy), and the uterus(hysterectomy). In some very early tumors, only the involved ovary willbe removed, especially in young women who wish to have children. Inadvanced disease, an attempt is made to remove all intra-abdominaldisease to enhance the effect of chemotherapy. There continues to be animportant need for effective treatment options for ovarian cancer.

There were an estimated 28,300 new cases of pancreatic cancer in theUnited States in 2000. Over the past 20 years, rates of pancreaticcancer have declined in men. Rates among women have remainedapproximately constant but may be beginning to decline. Pancreaticcancer caused an estimated 28,200 deaths in 2000 in the United States.Over the past 20 years, there has been a slight but significant decreasein mortality rates among men (about −0.9% per year) while rates haveincreased slightly among women.

Surgery, radiation therapy, and chemotherapy are treatment options forpancreatic cancer. These treatment options can extend survival and/orrelieve symptoms in many patients but are not likely to produce a curefor most. There is a significant need for additional therapeutic anddiagnostic options for pancreatic cancer.

SUMMARY OF THE INVENTION

The present invention relates to a gene, designated 98P4B6, that has nowbeen found to be over-expressed in the cancer(s) listed in Table I.Northern blot expression analysis of 98P4B6 gene expression in normaltissues shows a restricted expression pattern in adult tissues. Thenucleotide (FIG. 2) and amino acid (FIG. 2, and FIG. 3) sequences of98P4B6 are provided. The tissue-related profile of 98P4B6 in normaladult tissues, combined with the over-expression observed in the tissueslisted in Table I, shows that 98P4B6 is aberrantly over-expressed in atleast some cancers, and thus serves as a useful diagnostic,prophylactic, prognostic, and/or therapeutic target for cancers of thetissue(s) such as those listed in Table I.

The invention provides polynucleotides corresponding or complementary toall or part of the 98P4B6 genes, mRNAs, and/or coding sequences,preferably in isolated form, including polynucleotides encoding98P4B6-related proteins and fragments of4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more than 25contiguous amino acids; at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 80,85, 90, 95, 100 or more than 100 contiguous amino acids of a98P4B6-related protein, as well as the peptides/proteins themselves;DNA, RNA, DNA/RNA hybrids, and related molecules, polynucleotides oroligonucleotides complementary or having at least a 90% homology to the98P4B6 genes or mRNA sequences or parts thereof, and polynucleotides oroligonucleotides that hybridize to the 98P4B6 genes, mRNAs, or to98P4B6-encoding polynucleotides. Also provided are means for isolatingcDNAs and the genes encoding 98P4B6. Recombinant DNA moleculescontaining 98P4B6 polynucleotides, cells transformed or transduced withsuch molecules, and host-vector systems for the expression of 98P4B6gene products are also provided. The invention further providesantibodies that bind to 98P4B6 proteins and polypeptide fragmentsthereof, including polyclonal and monoclonal antibodies, murine andother mammalian antibodies, chimeric antibodies, humanized and fullyhuman antibodies, and antibodies labeled with a detectable marker ortherapeutic agent. In certain embodiments, there is a proviso that theentire nucleic acid sequence of FIG. 2 is not encoded and/or the entireamino acid sequence of FIG. 2 is not prepared. In certain embodiments,the entire nucleic acid sequence of FIG. 2 is encoded and/or the entireamino acid sequence of FIG. 2 is prepared, either of which are inrespective human unit dose forms.

The invention further provides methods for detecting the presence andstatus of 98P4B6 polynucleotides and proteins in various biologicalsamples, as well as methods for identifying cells that express 98P4B6. Atypical embodiment of this invention provides methods for monitoring98P4B6 gene products in a tissue or hematology sample having orsuspected of having some form of growth dysregulabton such as cancer.

The invention further provides various immunogenic or therapeuticcompositions and strategies for treating cancers that express 98P4B6such as cancers of tissues listed in Table I, including therapies aimedat inhibiting the transcription, translation, processing or function of98P4B6 as well as cancer vaccines. In one aspect, the invention providescompositions, and methods comprising them, for treating a cancer thatexpresses 98P4B6 in a human subject wherein the composition comprises acarrier suitable for human use and a human unit dose of one or more thanone agent that inhibits the production or function of 98P4B6.Preferably, the carrier is a uniquely human carrier. In another aspectof the invention, the agent is a moiety that is immunoreactive with98P4B6 protein. Non-limiting examples of such moieties include, but arenot limited to, antibodies (such as single chain, monoclonal,polyclonal, humanized, chimeric, or human antibodies), functionalequivalents thereof (whether naturally occurring or synthetic), andcombinations thereof. The antibodies can be conjugated to a diagnosticor therapeutic moiety. In another aspect, the agent is a small moleculeas defined herein.

In another aspect, the agent comprises one or more than one peptidewhich comprises a cytotoxic T lymphocyte (CTL) epitope that binds an HLAclass I molecule in a human to elicit a CTL response to 98P4B6 and/orone or more than one peptide which comprises a helper T lymphocyte (HTL)epitope which binds an HLA class II molecule in a human to elicit an HTLresponse. The peptides of the invention may be on the same or on one ormore separate polypeptide molecules. In a further aspect of theinvention, the agent comprises one or more than one nucleic acidmolecule that expresses one or more than one of the CTL or HTL responsestimulating peptides as described above. In yet another aspect of theinvention, the one or more than one nucleic acid molecule may express amoiety that is immunologically reactive with 98P4B6 as described above.The one or more than one nucleic acid molecule may also be, or encodes,a molecule that inhibits production of 98P4B6. Non-limiting examples ofsuch molecules include, but are not limited to, those complementary to anucleotide sequence essential for production of 98P4B6 (e.g. antisensesequences or molecules that form a triple helix with a nucleotide doublehelix essential for 98P4B6 production) or a ribozyme effective to lyse98P4B6 mRNA.

Note that to determine the starting position of any peptide set forth inTables VIII-XXI and XXII to XLIX (collectively HLA Peptide Tables)respective to its parental protein, e.g., variant 1, variant 2, etc.,reference is made to three factors: the particular variant, the lengthof the peptide in an HLA Peptide Table, and the Search Peptides in TableVII. Generally, a unique Search Peptide is used to obtain HLA peptidesof a particular for a particular variant. The position of each SearchPeptide relative to its respective parent molecule is listed in TableVII. Accordingly, if a Search Peptide begins at position “X”, one mustadd the value “X−1” to each position in Tables VIII-XXI and XXII to XLIXto obtain the actual position of the HLA peptides in their parentalmolecule. For example, if a particular Search Peptide begins at position150 of its parental molecule, one must add 150−1, i.e., 149 to each HLApeptide amino acid position to calculate the position of that amino acidin the parent molecule.

One embodiment of the invention comprises an HLA peptide, that occurs atleast twice in Tables VIII-XXI and XXII to XLIX collectively, or anoligonucleotide that encodes the HLA peptide. Another embodiment of theinvention comprises an HLA peptide that occurs at least once in TablesVIII-XXI and at least once in tables XXII to XLIX, or an oligonucleotidethat encodes the HLA peptide.

Another embodiment of the invention is antibody epitopes, which comprisea peptide regions, or an oligonucleotide encoding the peptide region,that has one two, three, four, or five of the following characteristics:

i) a peptide region of at least 5 amino acids of a particular peptide ofFIG. 3, in any whole number increment up to the full length of thatprotein in FIG. 3, that includes an amino acid position having a valueequal to or greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a valueequal to 1.0, in the Hydrophilicity profile of FIG. 5;

ii) a peptide region of at least 5 amino acids of a particular peptideof FIG. 3, in any whole number increment up to the full length of thatprotein in FIG. 3, that includes an amino acid position having a valueequal to or less than 0.5, 0.4, 0.3, 0.2, 0.1, or having a value equalto 0.0, in the Hydropathicity profile of FIG. 6;

iii) a peptide region of at least 5 amino acids of a particular peptideof FIG. 3, in any whole number increment up to the full length of thatprotein in FIG. 3, that includes an amino acid position having a valueequal to or greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a valueequal to 1.0, in the Percent Accessible Residues profile of FIG. 7;

iv) a peptide region of at least 5 amino acids of a particular peptideof FIG. 3, in any whole number increment up to the full length of thatprotein in FIG. 3, that includes an amino acid position having a valueequal to or greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a valueequal to 1.0, in the Average Flexibility profile of FIG. 8; or

v) a peptide region of at least 5 amino acids of a particular peptide ofFIG. 3, in any whole number increment up to the full length of thatprotein in FIG. 3, that includes an amino acid position having a valueequal to or greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a valueequal to 1.0, in the Beta-turn profile of FIG. 9.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. The 98P4B6 SSH sequence of 183 nucleotides.

FIG. 2. A) The cDNA and amino acid sequence of 98P4B6 variant 1 (alsocalled “98P4B6 v.1” or “98P4B6 variant 1”) is shown in FIG. 2A. Thestart methionine is underlined. The open reading frame extends fromnucleic acid 355-1719 including the stop codon.

B) The cDNA and amino acid sequence of 98P4B6 variant 2 (also called“98P4B6 v.2”) is shown in FIG. 2B. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 4-138including the stop codon.

C) The cDNA and amino acid sequence of 98P4B6 variant 3 (also called“98P4B6 v.3”) is shown in FIG. 2C. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 188-1552including the stop codon.

D) The cDNA and amino acid sequence of 98P4B6 variant 4 (also called“98P4B6 v.4”) is shown in FIG. 2D. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 318-1682including the stop codon.

E) The cDNA and amino acid sequence of 98P4B6 variant 5 (also called“98P4B6 v.5”) is shown in FIG. 2E. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 318-1577including the stop codon.

F) The cDNA and amino acid sequence of 98P4B6 variant 6 (also called“98P4B6 v.6”) is shown in FIG. 2F. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 318-1790including the stop codon.

G) The cDNA and amino acid sequence of 98P4B6 variant 7 (also called“98P4B6 v.7”) is shown in FIG. 2G. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 295-2025including the stop codon.

H) The cDNA and amino acid sequence of 98P4B6 variant 8 (also called“98P4B6 v.8”) is shown in FIG. 2H. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

I) The cDNA and amino acid sequence of 98P4B6 variant 9 (also called“98P4B6 v.9”) is shown in FIG. 21. The codon for the start methionine isunderlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

J) The cDNA and amino acid sequence of 98P4B6 variant 10 (also called“98P4B6 v.10”) is shown in FIG. 2J. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

K) The cDNA and amino acid sequence of 98P4B6 variant 11 (also called“98P4B6 v.11”) is shown in FIG. 2K. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

L) The cDNA and amino acid sequence of 98P4B6 variant 12 (also called“98P4B6 v.12”) is shown in FIG. 2L. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

M) The cDNA and amino acid sequence of 98P4B6 variant 13 (also called“98P4B6 v.13”) is shown in FIG. 2M. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

N) The cDNA and amino acid sequence of 98P4B6 variant 14 (also called“98P4B6 v.14”) is shown in FIG. 2N. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

O) The cDNA and amino acid sequence of 98P4B6 variant 15 (also called“98P4B6 v.15”) is shown in FIG. 20. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

P) The cDNA and amino acid sequence of 98P4B6 variant 16 (also called“98P4B6 v.16”) is shown in FIG. 2P. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

Q) The cDNA and amino acid sequence of 98P4B6 variant 17 (also called“98P4B6 v.17”) is shown in FIG. 2Q. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

R) The cDNA and amino acid sequence of 98P4B6 variant 18 (also called“98P4B6 v.18”) is shown in FIG. 2R. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

S) The cDNA and amino acid sequence of 98P4B6 variant 19 (also called“98P4B6 v.19”) is shown in FIG. 2S. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 355-1719including the stop codon.

T) The cDNA and amino acid sequence of 98P4B6 variant 20 (also called“98P4B6 v.20”) is shown in FIG. 2T. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 295-2025including the stop codon.

U) The cDNA and amino acid sequence of 98P4B6 variant 21 (also called“98P4B6 v.21”) is shown in FIG. 2U. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 295-2025including the stop codon.

V) The cDNA and amino acid sequence of 98P4B6 variant 22 (also called“98P4B6 v.22”) is shown in FIG. 2V. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 295-2025including the stop codon.

W) The cDNA and amino acid sequence of 98P4B6 variant 23 (also called“98P4B6 v.23”) is shown in FIG. 2W. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 295-2025including the stop codon.

X) The cDNA and amino acid sequence of 98P4B6 variant 24 (also called“98P4B6 v.24”) is shown in FIG. 2X. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 295-2025including the stop codon.

Y) The cDNA and amino acid sequence of 98P4B6 variant 25 (also called“98P4B6 v.25”) is shown in FIG. 2Y. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

Z) The cDNA and amino acid sequence of 98P4B6 variant 26 (also called“98P4B6 v.26”) is shown in FIG. 2Z. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AA) The cDNA and amino acid sequence of 98P4B6 variant 27 (also called“98P4B6 v.27”) is shown in FIG. 2AA. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AB) The cDNA and amino acid sequence of 98P4B6 variant 28 (also called“98P4B6 v.28”) is shown in FIG. 2AB. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AC) The cDNA and amino acid sequence of 98P4B6 variant 29 (also called“98P4B6 v.29”) is shown in FIG. 2AC. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AD) The cDNA and amino acid sequence of 98P4B6 variant 30 (also called“98P4B6 v.30”) is shown in FIG. 2AD. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AE) The cDNA and amino acid sequence of 98P4B6 variant 31 (also called“98P4B6 v.31”) is shown in FIG. 2AE. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AF) The cDNA and amino acid sequence of 98P4B6 variant 32 (also called“98P4B6 v.32”) is shown in FIG. 2AF. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AG) The cDNA and amino acid sequence of 98P4B6 variant 33 (also called“98P4B6 v.33”) is shown in FIG. 2AG. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AH) The cDNA and amino acid sequence of 98P4B6 variant 34 (also called“98P4B6 v.34”) is shown in FIG. 2AH. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AI) The cDNA and amino acid sequence of 98P4B6 variant 35 (also called“98P4B6 v.35”) is shown in FIG. 2AI. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AJ) The cDNA and amino acid sequence of 98P4B6 variant 36 (also called“98P4B6 v.36”) is shown in FIG. 2AJ. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AK) The cDNA and amino acid sequence of 98P4B6 variant 37 (also called“98P4B6 v.37”) is shown in FIG. 2AK. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

AL) The cDNA and amino acid sequence of 98P4B6 variant 38 (also called“98P4B6 v.38”) is shown in FIG. 2AL. The codon for the start methionineis underlined. The open reading frame extends from nucleic acid 394-1866including the stop codon.

FIG. 3.

A) The amino acid sequence of 98P4B6 v.1 is shown in FIG. 3A; it has 454amino acids.

B) The amino acid sequence of 98P4B6 v.2 is shown in FIG. 3B; it has 45amino acids.

C) The amino acid sequence of 98P4B6 v.5 is shown in FIG. 3C; it has 419amino acids.

D) The amino acid sequence of 98P4B6 v.6 is shown in FIG. 3D; it has 490amino acids.

E) The amino acid sequence of 98P4B6 v.7 is shown in FIG. 3E; it has 576amino acids.

F) The amino acid sequence of 98P4B6 v.8 is shown in FIG. 3F; it has 490amino acids.

G) The amino acid sequence of 98P4B6 v.13 is shown in FIG. 3G; it has454 amino acids.

H) The amino acid sequence of 98P4B6 v.14 is shown in FIG. 3H; it has454 amino acids.

I) The amino acid sequence of 98P4B6 v.21 is shown in FIG. 31; it has576 amino acids.

J) The amino acid sequence of 98P4B6 v.25 is shown in FIG. 3J; it has490 amino acids.

As used herein, a reference to 98P4B6 includes all variants thereof,including those shown in FIGS. 2, 3, 10, and 11, unless the contextclearly indicates otherwise.

FIG. 4. Comparison of 98P4B6 with known genes: Human STAMP1, human sixtransmembrane epithelial antigen of prostate 2 and mouse sixtransmembrane epithelial antigen of prostate 2.

FIG. 4(A) Alignment of 98P4B6 variant 1 to human STAMP1 (gi 15418732).

FIG. 4(B) Alignment of 98P4B6 variant 1 with human STEAP2 (gi:23308593).

FIG. 4(C) Alignment of 98P4B6 variant 1 with mouse STEAP2 (gi 28501136).

FIG. 4(D): Clustal Alignment of the three 98P4B6 variants, depictingthat 98P4B6 V1 B (SEQ ID NO: 94) contains an additional 62 aa at itsN-terminus relative to V1 (SEQ ID NO: 95), and that 98P4B6 V2 (SEQ IDNO: 96) carries a I to T point mutation at aa 225 relative to V1.

DETAILED DESCRIPTION OF THE INVENTION

Outline of Sections

-   -   I.) Definitions    -   II.) 98P4B6 Polynucleotides        -   II.A.) Uses of 98P4B6 Polynucleotides        -   II.A.1.) Monitoring of Genetic Abnormalities        -   II.A.2.) Antisense Embodiments        -   II.A.3.) Primers and Primer Pairs        -   II.A.4.) Isolation of 98P4B6-Encoding Nucleic Acid Molecules        -   II.A.5.) Recombinant Nucleic Acid Molecules and Host-Vector            Systems    -   III.) 98P4B6-Related Proteins        -   III.A.) Motif-bearing Protein Embodiments        -   III.B.) Expression of 98P4B6-Related Proteins        -   III.C.) Modifications of 98P4B6-Related Proteins        -   III.D.) Uses of 98P4B6-Related Proteins    -   IV.) 98P4B6 Antibodies    -   V.) 98P4B6 Cellular Immune Responses    -   VI.) 98P4B6 Transgenic Animals    -   VII.) Methods for the Detection of 98P4B6    -   VIII.) Methods for Monitoring the Status of 98P4B6-Related Genes        and Their Products    -   IX.) Identification of Molecules That Interact With 98P4B6    -   X.) Therapeutic Methods and Compositions        -   X.A.) Anti-Cancer Vaccines        -   X.B.) 98P4B6 as a Target for Antibody-Based Therapy        -   X.C.) 98P4B6 as a Target for Cellular Immune Responses            -   X.C.1. Minigene Vaccines            -   X.C.2. Combinations of CTL Peptides with Helper Peptides            -   X.C.3. Combinations of CTL Peptides with T Cell Priming                Agents            -   X.C.4. Vaccine Compositions Comprising DC Pulsed with                CTL and/or HTL Peptides        -   X.D.) Adoptive Immunotherapy        -   X.E.) Administration of Vaccines for Therapeutic or            Prophylactic Purposes    -   XI.) Diagnostic and Prognostic Embodiments of 98P4B6.    -   XII.) Inhibition of 98P4B6 Protein Function        -   XII.A.) Inhibition of 98P4B6 With Intracellular Antibodies        -   XII.B.) Inhibition of 98P4B6 with Recombinant Proteins        -   XII.C.) Inhibition of 98P4B6 Transcription or Translation        -   XII.D.) General Considerations for Therapeutic Strategies    -   XIII.) Identification, Characterization and Use of Modulators of        98P4B6    -   XIV.) KITS/Articles of Manufacture

I.) Definitions:

Unless otherwise defined, all terms of art, notations and otherscientific terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the art to which thisinvention pertains. In some cases, terms with commonly understoodmeanings are defined herein for clarity and/or for ready reference, andthe inclusion of such definitions herein should not necessarily beconstrued to represent a substantial difference over what is generallyunderstood in the art. Many of the techniques and procedures describedor referenced herein are well understood and commonly employed usingconventional methodology by those skilled in the art, such as, forexample, the widely utilized molecular cloning methodologies describedin Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd. edition(1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Asappropriate, procedures involving the use of commercially available kitsand reagents are generally carried out in accordance with manufacturerdefined protocols and/or parameters unless otherwise noted.

The terms “advanced prostate cancer”, “locally advanced prostatecancer”, “advanced disease” and “locally advanced disease” mean prostatecancers that have extended through the prostate capsule, and are meantto include stage C disease under the American Urological Association(AUA) system, stage C1-C2 disease under the Whitmore-Jewett system, andstage T3-T4 and N+ disease under the TNM (tumor, node, metastasis)system. In general, surgery is not recommended for patients with locallyadvanced disease, and these patients have substantially less favorableoutcomes compared to patients having clinically localized(organ-confined) prostate cancer. Locally advanced disease is clinicallyidentified by palpable evidence of induration beyond the lateral borderof the prostate, or asymmetry or induration above the prostate base.Locally advanced prostate cancer is presently diagnosed pathologicallyfollowing radical prostatectomy if the tumor invades or penetrates theprostatic capsule, extends into the surgical margin, or invades theseminal vesicles.

“Altering the native glycosylation pattern” is intended for purposesherein to mean deleting one or more carbohydrate moieties found innative sequence 98P4B6 (either by removing the underlying glycosylationsite or by deleting the glycosylation by chemical and/or enzymaticmeans), and/or adding one or more glycosylation sites that are notpresent in the native sequence 98P4B6. In addition, the phrase includesqualitative changes in the glycosylation of the native proteins,involving a change in the nature and proportions of the variouscarbohydrate moieties present.

The term “analog” refers to a molecule which is structurally similar orshares similar or corresponding attributes with another molecule (e.g. a98P4B6-related protein). For example, an analog of a 98P4B6 protein canbe specifically bound by an antibody or T cell that specifically bindsto 98P4B6.

The term “antibody” is used in the broadest sense. Therefore, an“antibody” can be naturally occurring or man-made such as monoclonalantibodies produced by conventional hybridoma technology. Anti-98P4B6antibodies comprise monoclonal and polyclonal antibodies as well asfragments containing the antigen-binding domain and/or one or morecomplementarity determining regions of these antibodies.

An “antibody fragment” is defined as at least a portion of the variableregion of the immunoglobulin molecule that binds to its target, i.e.,the antigen-binding region. In one embodiment it specifically coverssingle anti-98P4B6 antibodies and clones thereof (including agonist,antagonist and neutralizing antibodies) and anti-98P4B6 antibodycompositions with polyepitopic specificity.

The term “codon optimized sequences” refers to nucleotide sequences thathave been optimized for a particular host species by replacing anycodons having a usage frequency of less than about 20%. Nucleotidesequences that have been optimized for expression in a given hostspecies by elimination of spurious polyadenylation sequences,elimination of exon/intron splicing signals, elimination oftransposon-like repeats and/or optimization of GC content in addition tocodon optimization are referred to herein as an “expression enhancedsequences.”

A “combinatorial library” is a collection of diverse chemical compoundsgenerated by either chemical synthesis or biological synthesis bycombining a number of chemical “building blocks” such as reagents. Forexample, a linear combinatorial chemical library, such as a polypeptide(e.g., mutein) library, is formed by combining a set of chemicalbuilding blocks called amino acids in every possible way for a givencompound length (i.e., the number of amino acids in a polypeptidecompound). Numerous chemical compounds are synthesized through suchcombinatorial mixing of chemical building blocks (Gallop et al., J. Med.Chem. 37(9): 1233-1251 (1994)).

Preparation and screening of combinatorial libraries is well known tothose of skill in the art. Such combinatorial chemical librariesinclude, but are not limited to, peptide libraries (see, e.g., U.S. Pat.No. 5,010,175, Furka, Pept. Prot. Res. 37:487-493 (1991), Houghton etal., Nature, 354:84-88 (1991)), peptoids (PCT Publication No WO91/19735), encoded peptides (PCT Publication WO 93/20242), randombio-oligomers (PCT Publication WO 92/00091), benzodiazepines (U.S. Pat.No. 5,288,514), diversomers such as hydantoins, benzodiazepines anddipeptides (Hobbs et al., Proc. Nat. Acad. Sci. USA 90:6909-6913(1993)), vinylogous polypeptides (Hagihara et al., J. Amer. Chem. Soc.114:6568 (1992)), nonpeptidal peptidomimetics with a Beta-D-Glucosescaffolding (Hirschmann et al., J. Amer. Chem. Soc. 114:9217-9218(1992)), analogous organic syntheses of small compound libraries (Chenet al., J. Amer. Chem. Soc. 116:2661 (1994)), oligocarbarmates (Cho, etal., Science 261:1303 (1993)), and/or peptidyl phosphonates (Campbell etal., J. Org. Chem. 59:658 (1994)). See, generally, Gordon et al., J.Med. Chem. 37:1385 (1994), nucleic acid libraries (see, e.g.,Stratagene, Corp.), peptide nucleic acid libraries (see, e.g., U.S. Pat.No. 5,539,083), antibody libraries (see, e.g., Vaughn et al., NatureBiotechnology 14(3): 309-314 (1996), and PCT/US96/10287), carbohydratelibraries (see, e.g., Liang et al., Science 274:1520-1522 (1996), andU.S. Pat. No. 5,593,853), and small organic molecule libraries (see,e.g., benzodiazepines, Baum, C&EN, January 18, page 33 (1993);isoprenoids, U.S. Pat. No. 5,569,588; thiazolidinones andmetathiazanones, U.S. Pat. No. 5,549,974; pyrrolidines, U.S. Pat. Nos.5,525,735 and 5,519,134; morpholino compounds, U.S. Pat. No. 5,506, 337;benzodiazepines, U.S. Pat. No. 5,288,514; and the like).

Devices for the preparation of combinatorial libraries are commerciallyavailable (see, e.g., 357 NIPS, 390 NIPS, Advanced Chem Tech, LouisvilleKy.; Symphony, Rainin, Woburn, Mass.; 433A, Applied Biosystems, FosterCity, Calif.; 9050, Plus, Millipore, Bedford, NIA). A number ofwell-known robotic systems have also been developed for solution phasechemistries. These systems include automated workstations such as theautomated synthesis apparatus developed by Takeda Chemical Industries,LTD. (Osaka, Japan) and many robotic systems utilizing robotic arms(Zymate H, Zymark Corporation, Hopkinton, Mass.; Orca, Hewlett-Packard,Palo Alto, Calif.), which mimic the manual synthetic operationsperformed by a chemist. Any of the above devices are suitable for usewith the present invention. The nature and implementation ofmodifications to these devices (if any) so that they can operate asdiscussed herein will be apparent to persons skilled in the relevantart. In addition, numerous combinatorial libraries are themselvescommercially available (see, e.g., ComGenex, Princeton, N.J.; Asinex,Moscow, RU; Tripos, Inc., St. Louis, Mo.; ChemStar, Ltd, Moscow, RU; 3DPharmaceuticals, Exton, Pa.; Martek Biosciences, Columbia, Md.; etc.).

The term “cytotoxic agent” refers to a substance that inhibits orprevents the expression activity of cells, function of cells and/orcauses destruction of cells. The term is intended to include radioactiveisotopes chemotherapeutic agents, and toxins such as small moleculetoxins or enzymatically active toxins of bacterial, fungal, plant oranimal origin, including fragments and/or variants thereof. Examples ofcytotoxic agents include, but are not limited to auristatins,auromycins, maytansinoids, yttrium, bismuth, ricin, ricin A-chain,combrestatin, duocarmycins, dolostatins, doxorubicin, daunorubicin,taxol, cisplatin, cc1065, ethidium bromide, mitomycin, etoposide,tenoposide, vincristine, vinblastine, colchicine, dihydroxy anthracindione, actinomycin, diphtheria toxin, Pseudomonas exotoxin (PE) A, PE40,abrin, abrin A chain, modeccin A chain, alpha-sarcin, gelonin,mitogellin, retstrictocin, phenomycin, enomycin, curicin, crotin,calicheamicin, Sapaonaria officinalis inhibitor, and glucocorticoid andother chemotherapeutic agents, as well as radioisotopes such as At²¹¹,I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi^(212 or 213), P³² andradioactive isotopes of Lu including Lu¹⁷⁷. Antibodies may also beconjugated to an anti-cancer pro-drug activating enzyme capable ofconverting the pro-drug to its active form.

The “gene product” is sometimes referred to herein as a protein or mRNA.For example, a “gene product of the invention” is sometimes referred toherein as a “cancer amino acid sequence”, “cancer protein”, “protein ofa cancer listed in Table I”, a “cancer mRNA”, “mRNA of a cancer listedin Table I”, etc. In one embodiment, the cancer protein is encoded by anucleic acid of FIG. 2. The cancer protein can be a fragment, oralternatively, be the full-length protein to the fragment encoded by thenucleic acids of FIG. 2. In one embodiment, a cancer amino acid sequenceis used to determine sequence identity or similarity. In anotherembodiment, the sequences are naturally occurring allelic variants of aprotein encoded by a nucleic acid of FIG. 2. In another embodiment, thesequences are sequence variants as further described herein.

“High throughput screening” assays for the presence, absence,quantification, or other properties of particular nucleic acids orprotein products are well known to those of skill in the art. Similarly,binding assays and reporter gene assays are similarly well known. Thus,e.g., U.S. Pat. No. 5,559,410 discloses high throughput screeningmethods for proteins; U.S. Pat. No. 5,585,639 discloses high throughputscreening methods for nucleic acid binding (i.e., in arrays); while U.S.Pat. Nos. 5,576,220 and 5,541,061 disclose high throughput methods ofscreening for ligand/antibody binding.

In addition, high throughput screening systems are commerciallyavailable (see, e.g., Amersham Biosciences, Piscataway, N.J.; ZymarkCorp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio; BeckmanInstruments, Inc. Fullerton, Calif.; Precision Systems, Inc., Natick,Mass.; etc.). These systems typically automate entire procedures,including all sample and reagent pipetting, liquid dispensing, timedincubations, and final readings of the microplate in detector(s)appropriate for the assay. These configurable systems provide highthroughput and rapid start up as well as a high degree of flexibilityand customization. The manufacturers of such systems provide detailedprotocols for various high throughput systems. Thus, e.g., Zymark Corp.provides technical bulletins describing screening systems for detectingthe modulation of gene transcription, ligand binding, and the like.

The term “homolog” refers to a molecule which exhibits homology toanother molecule, by for example, having sequences of chemical residuesthat are the same or similar at corresponding positions.

“Human Leukocyte Antigen” or “HLA” is a human class I or class II MajorHistocompatibility Complex (MHC) protein (see, e.g., Stites, et al.,IMMUNOLOGY, 8^(TH) ED., Lange Publishing, Los Altos, Calif. (1994).

The terms “hybridize”, “hybridizing”, “hybridizes” and the like, used inthe context of polynucleotides, are meant to refer to conventionalhybridization conditions, preferably such as hybridization in 50%formamide/6×SSC/0.1% SDS/100 μg/ml ssDNA, in which temperatures forhybridization are above 37 degrees C. and temperatures for washing in0.1×SSC/0.1% SDS are above 55 degrees C.

The phrases “isolated” or “biologically pure” refer to material which issubstantially or essentially free from components which normallyaccompany the material as it is found in its native state. Thus,isolated peptides in accordance with the invention preferably do notcontain materials normally associated with the peptides in their in situenvironment. For example, a polynucleotide is said to be “isolated” whenit is substantially separated from contaminant polynucleotides thatcorrespond or are complementary to genes other than the 98P4B6 genes orthat encode polypeptides other than 98P4B6 gene product or fragmentsthereof. A skilled artisan can readily employ nucleic acid isolationprocedures to obtain an isolated 98P4B6 polynucleotide. A protein issaid to be “isolated,” for example, when physical, mechanical orchemical methods are employed to remove the 98P4B6 proteins fromcellular constituents that are normally associated with the protein. Askilled artisan can readily employ standard purification methods toobtain an isolated 98P4B6 protein. Alternatively, an isolated proteincan be prepared by chemical means.

The term “mammal” refers to any organism classified as a mammal,including mice, rats, rabbits, dogs, cats, cows, horses and humans. Inone embodiment of the invention, the mammal is a mouse. In anotherembodiment of the invention, the mammal is a human.

The terms “metastatic prostate cancer” and “metastatic disease” meanprostate cancers that have spread to regional lymph nodes or to distantsites, and are meant to include stage D disease under the AUA system andstage T×N×M+ under the TNM system. As is the case with locally advancedprostate cancer, surgery is generally not indicated for patients withmetastatic disease, and hormonal (androgen ablation) therapy is apreferred treatment modality. Patients with metastatic prostate cancereventually develop an androgen-refractory state within 12 to 18 monthsof treatment initiation. Approximately half of these androgen-refractorypatients die within 6 months after developing that status. The mostcommon site for prostate cancer metastasis is bone. Prostate cancer bonemetastases are often osteoblastic rather than osteolytic (i.e.,resulting in net bone formation). Bone metastases are found mostfrequently in the spine, followed by the femur, pelvis, rib cage, skulland humerus. Other common sites for metastasis include lymph nodes,lung, liver and brain. Metastatic prostate cancer is typically diagnosedby open or laparoscopic pelvic lymphadenectomy, whole body radionuclidescans, skeletal radiography, and/or bone lesion biopsy.

The term “modulator” or “test compound” or “drug candidate” orgrammatical equivalents as used herein describe any molecule, e.g.,protein, oligopeptide, small organic molecule, polysaccharide,polynucleotide, etc., to be tested for the capacity to directly orindirectly alter the cancer phenotype or the expression of a cancersequence, e.g., a nucleic acid or protein sequences, or effects ofcancer sequences (e.g., signaling, gene expression, protein interaction,etc.) In one aspect, a modulator will neutralize the effect of a cancerprotein of the invention. By “neutralize” is meant that an activity of aprotein is inhibited or blocked, along with the consequent effect on thecell. In another aspect, a modulator will neutralize the effect of agene, and its corresponding protein, of the invention by normalizinglevels of said protein. In preferred embodiments, modulators alterexpression profiles, or expression profile nucleic acids or proteinsprovided herein, or downstream effector pathways. In one embodiment, themodulator suppresses a cancer phenotype, e.g. to a normal tissuefingerprint. In another embodiment, a modulator induced a cancerphenotype. Generally, a plurality of assay mixtures is run in parallelwith different agent concentrations to obtain a differential response tothe various concentrations. Typically, one of these concentrationsserves as a negative control, i.e., at zero concentration or below thelevel of detection.

Modulators, drug candidates or test compounds encompass numerouschemical classes, though typically they are organic molecules,preferably small organic compounds having a molecular weight of morethan 100 and less than about 2,500 Daltons. Preferred small moleculesare less than 2000, or less than 1500 or less than 1000 or less than 500D. Candidate agents comprise functional groups necessary for structuralinteraction with proteins, particularly hydrogen bonding, and typicallyinclude at least an amine, carbonyl, hydroxyl or carboxyl group,preferably at least two of the functional chemical groups. The candidateagents often comprise cyclical carbon or heterocyclic structures and/oraromatic or polyaromatic structures substituted with one or more of theabove functional groups. Modulators also comprise biomolecules such aspeptides, saccharides, fatty acids, steroids, purines, pyrimidines,derivatives, structural analogs or combinations thereof. Particularlypreferred are peptides. One class of modulators are peptides, forexample of from about five to about 35 amino acids, with from about fiveto about 20 amino acids being preferred, and from about 7 to about 15being particularly preferred. Preferably, the cancer modulatory proteinis soluble, includes a non-transmembrane region, and/or, has anN-terminal Cys to aid in solubility. In one embodiment, the C-terminusof the fragment is kept as a free acid and the N-terminus is a freeamine to aid in coupling, i.e., to cysteine. In one embodiment, a cancerprotein of the invention is conjugated to an immunogenic agent asdiscussed herein. In one embodiment, the cancer protein is conjugated toBSA. The peptides of the invention, e.g., of preferred lengths, can belinked to each other or to other amino acids to create a longerpeptide/protein. The modulatory peptides can be digests of naturallyoccurring proteins as is outlined above, random peptides, or “biased”random peptides. In a preferred embodiment, peptide/protein-basedmodulators are antibodies, and fragments thereof, as defined herein.

Modulators of cancer can also be nucleic acids. Nucleic acid modulatingagents can be naturally occurring nucleic acids, random nucleic acids,or “biased” random nucleic acids. For example, digests of prokaryotic oreukaryotic genomes can be used in an approach analogous to that outlinedabove for proteins.

The term “monoclonal antibody” refers to an antibody obtained from apopulation of substantially homogeneous antibodies, i.e., the antibodiescomprising the population are identical except for possible naturallyoccurring mutations that are present in minor amounts.

A “motif”, as in biological motif of a 98P4B6-related protein, refers toany pattern of amino acids forming part of the primary sequence of aprotein, that is associated with a particular function (e.g.protein-protein interaction, protein-DNA interaction, etc) ormodification (e.g. that is phosphorylated, glycosylated or amidated), orlocalization (e.g. secretory sequence, nuclear localization sequence,etc.) or a sequence that is correlated with being immunogenic, eitherhumorally or cellularly. A motif can be either contiguous or capable ofbeing aligned to certain positions that are generally correlated with acertain function or property. In the context of HLA motifs, “motif”refers to the pattern of residues in a peptide of defined length,usually a peptide of from about 8 to about 13 amino acids for a class IHLA motif and from about 6 to about 25 amino acids for a class II HLAmotif, which is recognized by a particular HLA molecule. Peptide motifsfor HLA binding are typically different for each protein encoded by eachhuman HLA allele and differ in the pattern of the primary and secondaryanchor residues.

A “pharmaceutical excipient” comprises a material such as an adjuvant, acarrier, pH-adjusting and buffering agents, tonicity adjusting agents,wetting agents, preservative, and the like.

“Pharmaceutically acceptable” refers to a non-toxic, inert, and/orcomposition that is physiologically compatible with humans or othermammals.

The term “polynucleotide” means a polymeric form of nucleotides of atleast 10 bases or base pairs in length, either ribonucleotides ordeoxynucleotides or a modified form of either type of nucleotide, and ismeant to include single and double stranded forms of DNA and/or RNA. Inthe art, this term if often used interchangeably with “oligonucleotide”.A polynucleotide can comprise a nucleotide sequence disclosed hereinwherein thymidine (T), as shown for example in FIG. 2, can also beuracil (U); this definition pertains to the differences between thechemical structures of DNA and RNA, in particular the observation thatone of the four major bases in RNA is uracil (U) instead of thymidine(T).

The term “polypeptide” means a polymer of at least about 4, 5, 6, 7, or8 amino acids. Throughout the specification, standard three letter orsingle letter designations for amino acids are used. In the art, thisterm is often used interchangeably with “peptide” or “protein”.

An HLA “primary anchor residue” is an amino acid at a specific positionalong a peptide sequence which is understood to provide a contact pointbetween the immunogenic peptide and the HLA molecule. One to three,usually two, primary anchor residues within a peptide of defined lengthgenerally defines a “motif” for an immunogenic peptide. These residuesare understood to fit in close contact with peptide binding groove of anHLA molecule, with their side chains buried in specific pockets of thebinding groove. In one embodiment, for example, the primary anchorresidues for an HLA class I molecule are located at position 2 (from theamino terminal position) and at the carboxyl terminal position of a 8,9, 10, 11, or 12 residue peptide epitope in accordance with theinvention. Alternatively, in another embodiment, the primary anchorresidues of a peptide binds an HLA class II molecule are spaced relativeto each other, rather than to the termini of a peptide, where thepeptide is generally of at least 9 amino acids in length. The primaryanchor positions for each motif and supermotif are set forth in TableIV. For example, analog peptides can be created by altering the presenceor absence of particular residues in the primary and/or secondary anchorpositions shown in Table IV. Such analogs are used to modulate thebinding affinity and/or population coverage of a peptide comprising aparticular HLA motif or supermotif.

“Radioisotopes” include, but are not limited to the following(non-limiting exemplary uses are also set forth):

Examples Of Medical Isotopes

-   Isotope-   Description of Use    Actinium-225-   (AC-225)-   See Thorium-229 (Th-229)    Actinium-227-   (AC-227)-   Parent of Radium-223 (Ra-223) which is an alpha emitter used to    treat metastases in the skeleton resulting from cancer (i.e., breast    and prostate cancers), and cancer radioimmunotherapy    Bismuth-212-   (Bi-212)-   See Thorium-228 (Th-228)    Bismuth-213-   (Bi-213)-   See Thorium-229 (Th-229)    Cadmium-109-   (Cd-109)-   Cancer detection    Cobalt-60-   (Co-60)-   Radiation source for radiotherapy of cancer, for food irradiators,    and for sterilization of medical supplies    Copper-64-   (Cu-64)-   A positron emitter used for cancer therapy and SPECT imaging    Copper-67-   (Cu-67)-   Beta/gamma emitter used in cancer radioimmunotherapy and diagnostic    studies (i.e., breast and colon cancers, and lymphoma)    Dysprosium-166-   (Dy-166)-   Cancer radioimmunotherapy    Erbium-169-   (Er-169)-   Rheumatoid arthritis treatment, particularly for the small joints    associated with fingers and toes    Europium-152-   (Eu-152)-   Radiation source for food irradiation and for sterilization of    medical supplies    Europium-154-   (Eu-154)-   Radiation source for food irradiation and for sterilization of    medical supplies    Gadolinium-153-   (Gd-153)-   Osteoporosis detection and nuclear medical quality assurance devices    Gold-198-   (Au-198)-   Implant and intracavity therapy of ovarian, prostate, and brain    cancers    Holmium-166-   (Ho-166)-   Multiple myeloma treatment in targeted skeletal therapy, cancer    radioimmunotherapy, bone marrow ablation, and rheumatoid arthritis    treatment    Iodine-125-   (1-125)-   Osteoporosis detection, diagnostic imaging, tracer drugs, brain    cancer treatment, radiolabeling, tumor imaging, mapping of receptors    in the brain, interstitial radiation therapy, brachytherapy for    treatment of prostate cancer, determination of glomerular filtration    rate (GFR), determination of plasma volume, detection of deep vein    thrombosis of the legs    Iodine-131-   (1-131)-   Thyroid function evaluation, thyroid disease detection, treatment of    thyroid cancer as well as other non-malignant thyroid diseases    (i.e., Graves disease, goiters, and hyperthyroidism), treatment of    leukemia, lymphoma, and other forms of cancer (e.g., breast cancer)    using radioimmunotherapy    Iridium-192-   (Ir-192)-   Brachytherapy, brain and spinal cord tumor treatment, treatment of    blocked arteries (i.e., arteriosclerosis and restenosis), and    implants for breast and prostate tumors    Lutetium-177-   (Lu-177)-   Cancer radioimmunotherapy and treatment of blocked arteries (i.e.,    arteriosclerosis and restenosis)    Molybdenum-99-   (Mo-99)-   Parent of Technetium-99m (Tc-99m) which is used for imaging the    brain, liver, lungs, heart, and other organs. Currently, Tc-99m is    the most widely used radioisotope used for diagnostic imaging of    various cancers and diseases involving the brain, heart, liver,    lungs; also used in detection of deep vein thrombosis of the legs    Osmium-194-   (Os-194)-   Cancer radioimmunotherapy    Palladium-103-   (Pd-103)-   Prostate cancer treatment    Platinum-195m-   (Pt-195m)-   Studies on biodistribution and metabolism of cisplatin, a    chemotherapeutic drug    Phosphorus-32-   (P-32)-   Polycythemia rubra vera (blood cell disease) and leukemia treatment,    bone cancer diagnosis/treatment; colon, pancreatic, and liver cancer    treatment; radiolabeling nucleic acids for in vitro research,    diagnosis of superficial tumors, treatment of blocked arteries    (i.e., arteriosclerosis and restenosis), and intracavity therapy    Phosphorus-33-   (P-33)-   Leukemia treatment, bone disease diagnosis/treatment, radiolabeling,    and treatment of blocked arteries (i.e., arteriosclerosis and    restenosis)    Radium-223-   (Ra-223)-   See Actinium-227 (Ac-227)    Rhenium-186-   (Re-186)-   Bone cancer pain relief, rheumatoid arthritis treatment, and    diagnosis and treatment of lymphoma and bone, breast, colon, and    liver cancers using radioimmunotherapy    Rhenium-188-   (Re-188)-   Cancer diagnosis and treatment using radioimmunotherapy, bone cancer    pain relief, treatment of rheumatoid arthritis, and treatment of    prostate cancer    Rhodium-105-   (Rh-105)-   Cancer radioimmunotherapy    Samarium-145-   (Sm-145)-   Ocular cancer treatment    Samarium-153-   (Sm-153)-   Cancer radioimmunotherapy and bone cancer pain relief    Scandium-47-   (Sc-47)-   Cancer radioimmunotherapy and bone cancer pain relief    Selenium-75-   (Se-75)-   Radiotracer used in brain studies, imaging of adrenal cortex by    gamma-scintigraphy, lateral locations of steroid secreting tumors,    pancreatic scanning, detection of hyperactive parathyroid glands,    measure rate of bile acid loss from the endogenous pool    Strontium-85-   (Sr-85)-   Bone cancer detection and brain scans    Strontium-89-   (Sr-89)-   Bone cancer pain relief, multiple myeloma treatment, and    osteoblastic therapy    Technetium-99m-   (Tc-99m)-   See Molybdenum-99 (Mo-99)    Thorium-228-   (Th-228)-   Parent of Bismuth-212 (Bi-212) which is an alpha emitter used in    cancer radioimmunotherapy    Thorium-229-   (Th-229)-   Parent of Actinium-225 (Ac-225) and grandparent of Bismuth-213    (Bi-213) which are alpha emitters used in cancer radioimmunotherapy    Thulium-170-   (Tm-170)-   Gamma source for blood irradiators, energy source for implanted    medical devices    Tin-117m-   (Sn-1i17m)-   Cancer immunotherapy and bone cancer pain relief    Tungsten-188-   (W-188)-   Parent for Rhenium-188 (Re-188) which is used for cancer    diagnostics/treatment, bone cancer pain relief, rheumatoid arthritis    treatment, and treatment of blocked arteries (i.e., arteriosclerosis    and restenosis)    Xenon-127-   (Xe-127)-   Neuroimaging of brain disorders, high resolution SPECT studies,    pulmonary function tests, and cerebral blood flow studies    Ytterbium-175-   (Yb-175)-   Cancer radioimmunotherapy    Yttrium-90-   (Y-90)-   Microseeds obtained from irradiating Yttrium-89 (Y-89) for liver    cancer treatment    Yttrium-91-   (Y-91)-   A gamma-emitting label for Yttrium-90 (Y-90) which is used for    cancer radioimmunotherapy (i.e., lymphoma, breast, colon, kidney,    lung, ovarian, prostate, pancreatic, and inoperable liver cancers)

By “randomized” or grammatical equivalents as herein applied to nucleicacids and proteins is meant that each nucleic acid and peptide consistsof essentially random nucleotides and amino acids, respectively. Theserandom peptides (or nucleic acids, discussed herein) can incorporate anynucleotide or amino acid at any position. The synthetic process can bedesigned to generate randomized proteins or nucleic acids, to allow theformation of all or most of the possible combinations over the length ofthe sequence, thus forming a library of randomized candidate bioactiveproteinaceous agents.

In one embodiment, a library is “fully randomized,” with no sequencepreferences or constants at any position. In another embodiment, thelibrary is a “biased random” library. That is, some positions within thesequence either are held constant, or are selected from a limited numberof possibilities. For example, the nucleotides or amino acid residuesare randomized within a defined class, e.g., of hydrophobic amino acids,hydrophilic residues, sterically biased (either small or large)residues, towards the creation of nucleic acid binding domains, thecreation of cysteines, for cross-linking, prolines for SH-3 domains,serines, threonines, tyrosines or histidines for phosphorylation sites,etc., or to purines, etc.

A “recombinant” DNA or RNA molecule is a DNA or RNA molecule that hasbeen subjected to molecular manipulation in vitro.

Non-limiting examples of small molecules include compounds that bind orinteract with 98P4B6, ligands including hormones, neuropeptides,chemokines, odorants, phospholipids, and functional equivalents thereofthat bind and preferably inhibit 98P4B6 protein function. Suchnon-limiting small molecules preferably have a molecular weight of lessthan about 10 kDa, more preferably below about 9, about 8, about 7,about 6, about 5 or about 4 kDa. In certain embodiments, small moleculesphysically associate with, or bind, 98P4B6 protein; are not found innaturally occurring metabolic pathways; and/or are more soluble inaqueous than non-aqueous solutions

“Stringency” of hybridization reactions is readily determinable by oneof ordinary skill in the art, and generally is an empirical calculationdependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured nucleic acidsequences to reanneal when complementary strands are present in anenvironment below their melting temperature. The higher the degree ofdesired homology between the probe and hybridizable sequence, the higherthe relative temperature that can be used. As a result, it follows thathigher relative temperatures would tend to make the reaction conditionsmore stringent, while lower temperatures less so. For additional detailsand explanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley IntersciencePublishers, (1995).

“Stringent conditions” or “high stringency conditions”, as definedherein, are identified by, but not limited to, those that: (1) employlow ionic strength and high temperature for washing, for example 0.015 Msodium chloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at50° C.; (2) employ during hybridization a denaturing agent, such asformamide, for example, 50% (v/v) formamide with 0.1% bovine serumalbumin/0.1% Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphatebuffer at pH 6.5 with 750 mM sodium chloride, 75 mM sodium citrate at42° C.; or (3) employ 50% formamide, 5×SSC (0.75 M NaCl, 0.075 M sodiumcitrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate,5×Denhardt's solution, sonicated salmon sperm DNA (50 μg/ml), 0.1% SDS,and 10% dextran sulfate at 42° C., with washes at 42° C. in 0.2×SSC(sodium chloride/sodium. citrate) and 50% formamide at 55° C., followedby a high-stringency wash consisting of 0.1×SSC containing EDTA at 55°C. “Moderately stringent conditions” are described by, but not limitedto, those in Sambrook et al., Molecular Cloning: A Laboratory Manual,New York: Cold Spring Harbor Press, 1989, and include the use of washingsolution and hybridization conditions (e.g., temperature, ionic strengthand %SDS) less stringent than those described above. An example ofmoderately stringent conditions is overnight incubation at 37° C. in asolution comprising: 20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodiumcitrate), 50 mM sodium phosphate (pH 7.6), 5×Denhardt's solution, 10%dextran sulfate, and 20 mg/mL denatured sheared salmon sperm DNA,followed by washing the filters in 1×SSC at about 37-50° C. The skilledartisan will recognize how to adjust the temperature, ionic strength,etc. as necessary to accommodate factors such as probe length and thelike.

An HLA “supermotif” is a peptide binding specificity shared by HLAmolecules encoded by two or more HLA alleles. Overall phenotypicfrequencies of HLA-supertypes in different ethnic populations are setforth in Table IV (F). The non-limiting constituents of varioussupetypes are as follows:

A2: A*0201, A*0202, A*0203, A*0204, A* 0205, A*0206, A*6802, A*6901,A*0207

A3: A3, A11, A31,A*3301, A*6801,A*0301, A*1101, A*3101

B7: B7, B*3501-03, B*51, B*5301, B*5401, B*5501, B*5502, B*5601, B*6701,B*7801, B*0702, B*5101, B*5602

B44: B*3701, B*4402, B*4403, B*60 (B*4001), B61 (B*4006)

A1: A*0102, A*2604, A*3601, A*4301, A*8001

A24: A*24, A*30, A*2403, A*2404, A*3002, A*3003

B27: B*1401-02, B*1503, B*1509, B*1510, B*1518, B*3801-02, B*3901,B*3902, B*3903-04, B*4801-02, B*7301, B*2701-08

B58: B*1516, B*1517, B*5701, B*5702, B58

B62: B*4601, B52, B*1501 (B62), B*1502 (B75), B*1513 (B77)

Calculated population coverage afforded by different HLA-supertypecombinations are set forth in Table IV (G).

As used herein “to treat” or “therapeutic” and grammatically relatedterms, refer to any improvement of any consequence of disease, such asprolonged survival, less morbidity, and/or a lessening of side effectswhich are the byproducts of an alternative therapeutic modality; fulleradication of disease is not required.

A “transgenic animal” (e.g., a mouse or rat) is an animal having cellsthat contain a transgene, which transgene was introduced into the animalor an ancestor of the animal at a prenatal, e.g., an embryonic stage. A“transgene” is a DNA that is integrated into the genome of a cell fromwhich a transgenic animal develops.

As used herein, an HLA or cellular immune response “vaccine” is acomposition that contains or encodes one or more peptides of theinvention. There are numerous embodiments of such vaccines, such as acocktail of one or more individual peptides; one or more peptides of theinvention comprised by a polyepitopic peptide; or nucleic acids thatencode such individual peptides or polypeptides, e.g., a minigene thatencodes a polyepitopic peptide. The “one or more peptides” can includeany whole unit integer from 1-150 or more, e.g., at least 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,105,110, 115, 120, 125, 130,135,140, 145, or 150 or more peptides of theinvention. The peptides or polypeptides can optionally be modified, suchas by lipidation, addition of targeting or other sequences. HLA class Ipeptides of the invention can be admixed with, or linked to, HLA classII peptides, to facilitate activation of both cytotoxic T lymphocytesand helper T lymphocytes. HLA vaccines can also comprise peptide-pulsedantigen presenting cells, e.g., dendritic cells.

The term “variant” refers to a molecule that exhibits a variation from adescribed type or norm, such as a protein that has one or more differentamino add residues in the corresponding position(s) of a specificallydescribed protein (e.g. the 98P4B6 protein shown in FIG. 2 or FIG. 3. Ananalog is an example of a variant protein. Splice isoforms and singlenucleotides polymorphisms (SNPs) are further examples of variants.

The “98P4B6-related proteins” of the invention include thosespecifically identified herein, as well as allelic variants,conservative substitution variants, analogs and homologs that can beisolated/generated and characterized without undue experimentationfollowing the methods outlined herein or readily available in the art.Fusion proteins that combine parts of different 98P4B6 proteins orfragments thereof, as well as fusion proteins of a 98P4B6 protein and aheterologous polypeptide are also included. Such 98P4B6 proteins arecollectively referred to as the 98P4B6-related proteins, the proteins ofthe invention, or 98P4B6. The term “98P4B6-related protein” refers to apolypeptide fragment or a 98P4B6 protein sequence of 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or morethan 25 amino acids; or, at least 30, 35, 40, 45, 50, 55, 60, 65, 70,80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150,155, 160, 165, 170, 175, 180, 185,190,195, 200, 225, 250, 275, 300, 325,350, 375, 400, 425, 450, 475, 500, 525, 550, 575, or 576 or more aminoacids.

II.) 98P4B6 Polynucleotides

One aspect of the invention provides polynucleotides corresponding orcomplementary to all or part of a 98P4B6 gene, mRNA, and/or codingsequence, preferably in isolated form, including polynucleotidesencoding a 98P4B6-related protein and fragments thereof, DNA, RNA,DNA/RNA hybrid, and related molecules, polynucleotides oroligonucleotides complementary to a 98P4B6 gene or mRNA sequence or apart thereof, and polynucleotides or oligonucleotides that hybridize toa 98P4B6 gene, mRNA, or to a 98P4B6 encoding polynucleotide(collectively, “98P4B6 polynucleotides”). In all instances when referredto in this section, T can also be U in FIG. 2.

Embodiments of a 98P4B6 polynucleotide include: a 98P4B6 polynucleotidehaving the sequence shown in FIG. 2, the nucleotide sequence of 98P4B6as shown in FIG. 2 wherein T is U; at least 10 contiguous nucleotides ofa polynucleotide having the sequence as shown in FIG. 2; or, at least 10contiguous nucleotides of a polynucleotide having the sequence as shownin FIG. 2 where T is U. For example, embodiments of 98P4B6 nucleotidescomprise, without limitation:

(I) a polynucleotide comprising, consisting essentially of, orconsisting of a sequence as shown in FIG. 2, wherein T can also be U;

(II) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2A, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(III) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2B, from nucleotide residuenumber 4 through nucleotide residue number 138, including the stopcodon, wherein T can also be U;

(IV) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2C, from nucleotide residuenumber 188 through nucleotide residue number 1552, including the a stopcodon, wherein T can also be U;

(V) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2D, from nucleotide residuenumber 318 through nucleotide residue number 1682, including the stopcodon, wherein T can also be U;

(VI) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2E, from nucleotide residuenumber 318 through nucleotide residue number 1577, including the stopcodon, wherein T can also be U;

(VII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2F, from nucleotide residuenumber 318 through nucleotide residue number 1790, including the stopcodon, wherein T can also be U;

(VIII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2G, from nucleotide residuenumber 295 through nucleotide residue number 2025, including the stopcodon, wherein T can also be U;

(IX) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2H, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(X) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 21, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XI) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2J, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2K, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XIII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2L, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XIV) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2M, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XV) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2N, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XVI) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 20, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XVII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2P, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XVIII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2Q, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XIX) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2R, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XX) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2S, from nucleotide residuenumber 355 through nucleotide residue number 1719, including the stopcodon, wherein T can also be U;

(XXI) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2T, from nucleotide residuenumber 295 through nucleotide residue number 2025, including the stopcodon, wherein T can also be U;

(XXII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2U, from nucleotide residuenumber 295 through nucleotide residue number 2025, including the stopcodon, wherein T can also be U;

(XXIII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2V, from nucleotide residuenumber 295 through nucleotide residue number 2025, including the stopcodon, wherein T can also be U;

(XXIV) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2W, from nucleotide residuenumber 295 through nucleotide residue number 2025, including the stopcodon, wherein T can also be U;

(XXV) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2X, from nucleotide residuenumber 295 through nucleotide residue number 2025, including the stopcodon, wherein T can also be U;

(XXVI) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2Y, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXVII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2Z, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXVIII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2M, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXIX) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AB, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXX) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AC, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXI) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AD, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AE, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXIII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AF, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXIV) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AG, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXV) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AH, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXVI) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AI, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXVII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AJ, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXVIII) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AK, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XXXIX) a polynucleotide comprising, consisting essentially of, orconsisting of the sequence as shown in FIG. 2AL, from nucleotide residuenumber 394 through nucleotide residue number 1866, including the stopcodon, wherein T can also be U;

(XL) a polynucleotide that encodes a 98P4B6-related protein that is atleast 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% homologous to anentire amino acid sequence shown in FIG. 2A-AL;

(XLI) a polynucleotide that encodes a 98P4B6-related protein that is atleast 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical to anentire amino acid sequence shown in FIG. 2A-AL;

(XLII) a polynucleotide that encodes at least one peptide set forth inTables VIII-XXI and XXII-XLIX;

(XLIII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3A, 3G, and 3H in any whole number increment up to 454 that includes atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 aminoacid position(s) having a value greater than 0.5 in the Hydrophilicityprofile of FIG. 5;

(XLIV) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3A, 3G, and 3H in any whole number increment up to 454 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value less than 0.5 in the Hydropathicity profileof FIG. 6;

(XLV) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3A, 3G, and 3H in any whole number increment up to 454 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Percent AccessibleResidues profile of FIG. 7;

(XLVI) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3A, 3G, and 3H in any whole number increment up to 454 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Average Flexibilityprofile of FIG. 8;

(XLVII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3A, 3G, and 3H in any whole number increment up to 454 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Beta-turn profile ofFIG. 9;

(XLVIII) a polynucleotide that encodes a peptide region of at least 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide ofFIG. 3B in any whole number increment up to 45 that includes 1, 2, 3,4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s)having a value greater than 0.5 in the Hydrophilicity profile of FIG. 5;

(XLIX) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3B in any whole number increment up to45 that includes 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) having avalue less than 0.5 in the Hydropathicity profile of FIG. 6;

(L) a polynucleotide that encodes a peptide region of at least 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3B in any whole number increment up to 45 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value greater than 0.5 in the Percent Accessible Residues profile ofFIG. 7;

(LI) a polynucleotide that encodes a peptide region of at least 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3B in any whole number increment up to 45 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value greater than 0.5 in the Average Flexibility profile of FIG. 8;

(LII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3B in any whole number increment up to 45 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value greater than 0.5 in the Beta-turn profile of FIG. 9

(LIII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3C in any whole number increment up to 419 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10; 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value greater than 0.5 in the Hydrophilicity profile of FIG. 5;

(LIV) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3C in any whole number increment up to 419 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value less than 0.5 in the Hydropathicity profile of FIG. 6;

(LV) a polynucleotide that encodes a peptide region of at least 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3C in any whole number increment up to 419 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value greater than 0.5 in the Percent Accessible Residues profile ofFIG. 7;

(LVI) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3C in any whole number increment up to 419 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value greater than 0.5 in the Average Flexibility profile of FIG. 8;

(LVII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIG.3C in any whole number increment up to 419 that includes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acid position(s) havinga value greater than 0.5 in the Beta-turn profile of FIG. 9

(LVIII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3D, 3F, and 3J in any whole number increment up to 490 that includes 1,2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Hydrophilicityprofile of FIG. 5;

(LIX) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3D, 3F, and 3J in any whole number increment up to 490 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value less than 0.5 in the Hydropathicity profileof FIG. 6;

(LX) a polynucleotide that encodes a peptide region of at least 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3D, 3F, and 3J in any whole number increment up to 490 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Percent AccessibleResidues profile of FIG. 7;

(LXI) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3D, 3F, and 3J in any whole number increment up to 490 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Average Flexibilityprofile of FIG. 8;

(LXII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3D, 3F, and 3J in any whole number increment up to 490 that includes 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Beta-turn profile ofFIG. 9

(LXIII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3E and 3I in any whole number increment up to 576 that includes 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Hydrophilicityprofile of FIG. 5;

(LXIV) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3E and 3I in any whole number increment up to 576 that includes 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value less than 0.5 in the Hydropathicity profileof FIG. 6;

(LXV) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3E and 3I in any whole number increment up to 576 that includes 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Percent AccessibleResidues profile of FIG. 7;

(LXVI) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3E and 3I in any whole number increment up to 576 that includes 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Average Flexibilityprofile of FIG. 8;

(LXVII) a polynucleotide that encodes a peptide region of at least 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acids of a peptide of FIGS.3E and 3I in any whole number increment up to 576 that includes 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Beta-turn profile ofFIG. 9

(LXVIII) a polynucleotide that is fully complementary to apolynucleotide of any one of (I)-(LXVII).

(LXIX) a peptide that is encoded by any of (I) to (LXVIII); and

(LXX) a composition comprising a polynucleotide of any of (I)-(LXVIII)or peptide of (LXIX) together with a pharmaceutical excipient and/or ina human unit dose form.

(LXXI) a method of using a polynucleotide of any (I)-(LXVIII) or peptideof (LXIX) or a composition of (LXX) in a method to modulate a cellexpressing 98P4B6,

(LXXII) a method of using a polynucleotide of any (I)-(LXVIII) orpeptide of (LXIX) or a composition of (LXX) in a method to diagnose,prophylax, prognose, or treat an individual who bears a cell expressing98P4B6

(LXXIII) a method of using a polynucleotide of any (I)-(LXVIII) orpeptide of (LXIX) or a composition of (LXX) in a method to diagnose,prophylax, prognose, or treat an individual who bears a cell expressing98P4B6, said cell from a cancer of a tissue listed in Table I;

(LXXIV) a method of using a polynucleotide of any (I)-(LXVIII) orpeptide of (LXIX) or a composition of (LXX) in a method to diagnose,prophylax, prognose, or treat a cancer;

(LXXV) a method of using a polynucleotide of any (I)-(LXVIII) or peptideof (LXIX) or a composition of (LXX) in a method to diagnose, prophylax,prognose, or treat a cancer of a tissue listed in Table I; and,

(LXXVI) a method of using a polynucleotide of any (I)-(LXVIII) orpeptide of (LXIX) or a composition of (LXX) in a method to identify orcharacterize a modulator of a cell expressing 98P4B6.

As used herein, a range is understood to disclose specifically all wholeunit positions thereof.

Typical embodiments of the invention disclosed herein include 98P4B6polynucleotides that encode specific portions of 98P4B6 mRNA sequences(and those which are complementary to such sequences) such as those thatencode the proteins and/or fragments thereof, for example:

(a) 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22,23,24, 25, 30, 35, 40,45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170,175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400,410, 420, 430, 440, 450 or 454 or more contiguous amino acids of 98P4B6variant 1; the maximal lengths relevant for other variants are: variant2, 44 amino acids; variant 5, 419 amino acids, variant 6, 490 aminoacids, variant 7, 576 amino acids, variant 8, 490 amino acids, variant13, 454 amino acids, variant 14, 454 amino acids, variant 21, 576 aminoacids, and variant 25, 490 amino acids.

For example, representative embodiments of the invention disclosedherein include: polynucleotides and their encoded peptides themselvesencoding about amino acid 1 to about amino acid 10 of the 98P4B6 proteinshown in FIG. 2 or FIG. 3, polynucleotides encoding about amino acid 10to about amino acid 20 of the 98P4B6 protein shown in FIG. 2 or FIG. 3,polynucleotides encoding about amino acid 20 to about amino acid 30 ofthe 98P4B6 protein shown in FIG. 2 or FIG. 3, polynucleotides encodingabout amino acid 30 to about amino acid 40 of the 98P4B6 protein shownin FIG. 2 or FIG. 3, polynucleotides encoding about amino acid 40 toabout amino acid 50 of the 98P4B6 protein shown in FIG. 2 or FIG. 3,polynucleotides encoding about amino acid 50 to about amino acid 60 ofthe 98P4B6 protein shown in FIG. 2 or FIG. 3, polynucleotides encodingabout amino acid 60 to about amino acid 70 of the 98P4B6 protein shownin FIG. 2 or FIG. 3, polynucleotides encoding about amino acid 70 toabout amino acid 80 of the 98P4B6 protein shown in FIG. 2 or FIG. 3,polynucleotides encoding about amino acid 80 to about amino acid 90 ofthe 98P4B6 protein shown in FIG. 2 or FIG. 3, polynucleotides encodingabout amino acid 90 to about amino acid 100 of the 98P4B6 protein shownin FIG. 2 or FIG. 3, in increments of about 10 amino acids, ending atthe carboxyl terminal amino acid set forth in FIG. 2 or FIG. 3.Accordingly, polynucleotides encoding portions of the amino acidsequence (of about 10 amino acids), of amino acids, 100 through thecarboxyl terminal amino acid of the 98P4B6 protein are embodiments ofthe invention. Wherein it is understood that each particular amino acidposition discloses that position plus or minus five amino acid residues.

Polynucleotides encoding relatively long portions of a 98P4B6 proteinare also within the scope of the invention. For example, polynucleotidesencoding from about amino acid 1 (or 20 or 30 or 40 etc.) to about aminoacid 20, (or 30, or 40 or 50 etc.) of the 98P4B6 protein “or variant”shown in FIG. 2 or FIG. 3 can be generated by a variety of techniqueswell known in the art. These polynucleotide fragments can include anyportion of the 98P4B6 sequence as shown in FIG. 2.

Additional illustrative embodiments of the invention disclosed hereininclude 98P4B6 polynucleotide fragments encoding one or more of thebiological motifs contained within a 98P4B6 protein “or variant”sequence, including one or more of the motif-bearing subsequences of a98P4B6 protein “or variant” set forth in Tables VIII-XXI and XXII-XLIX.In another embodiment, typical polynucleotide fragments of the inventionencode one or more of the regions of 98P4B6 protein or variant thatexhibit homology to a known molecule. In another embodiment of theinvention, typical polynucleotide fragments can encode one or more ofthe 98P4B6 protein or variant N-glycosylation sites, cAMP andcGMP-dependent protein kinase phosphorylation sites, casein kinase IIphosphorylation sites or N-myristoylation site and amidation sites.

Note that to determine the starting position of any peptide set forth inTables VIII-XXI and Tables XXII to XLIX (collectively HLA PeptideTables) respective to its parental protein, e.g., variant 1, variant 2,etc., reference is made to three factors: the particular variant, thelength of the peptide in an HLA Peptide Table, and the Search Peptideslisted in Table VII. Generally, a unique Search Peptide is used toobtain HLA peptides for a particular variant. The position of eachSearch Peptide relative to its respective parent molecule is listed inTable VII. Accordingly, if a Search Peptide begins at position “X”, onemust add the value “X minus 1” to each position in Tables VIII-XXI andTables XXII-IL to obtain the actual position of the HLA peptides intheir parental molecule. For example if a particular Search Peptidebegins at position 150 of its parental molecule, one must add 150-1,i.e., 149 to each HLA peptide amino acid position to calculate theposition of that amino acid in the parent molecule.

II.A.) Uses of 98P4B6 Polynucleotides

II.A.1.) Monitoring of Genetic Abnormalities

The polynucleotides of the preceding paragraphs have a number ofdifferent specific uses. The human 98P4B6 gene maps to the chromosomallocation set forth in the Example entitled “Chromosomal Mapping of98P4B6.” For example, because the 98P4B6 gene maps to this chromosome,polynucleotides that encode different regions of the 98P4B6 proteins areused to characterize cytogenetic abnormalities of this chromosomallocale, such as abnormalities that are identified as being associatedwith various cancers. In certain genes, a variety of chromosomalabnormalities including rearrangements have been identified as frequentcytogenetic abnormalities in a number of different cancers (see e.g.Krajinovic et al., Mutat. Res. 382(3-4): 81-83 (1998); Johansson et al.,Blood 86(10): 3905-3914 (1995) and Finger et al., P.N.A.S. 85(23):9158-9162 (1988)). Thus, polynucleotides encoding specific regions ofthe 98P4B6 proteins provide new tools that can be used to delineate,with greater precision than previously possible, cytogeneticabnormalities in the chromosomal region that encodes 98P4B6 that maycontribute to the malignant phenotype. In this context, thesepolynucleotides satisfy a need in the art for expanding the sensitivityof chromosomal screening in order to identify more subtle and lesscommon chromosomal abnormalities (see e.g. Evans et al., Am. J. Obstet.Gynecol 171(4): 1055-1057 (1994)).

Furthermore, as 98P4B6 was shown to be highly expressed in prostate andother cancers, 98P4B6 polynucleotides are used in methods assessing thestatus of 98P4B6 gene products in normal versus cancerous tissues.Typically, polynucleotides that encode specific regions of the 98P4B6proteins are used to assess the presence of perturbations (such asdeletions, insertions, point mutations, or alterations resulting in aloss of an antigen etc.) in specific regions of the 98P4B6 gene, such asregions containing one or more motifs. Exemplary assays include bothRT-PCR assays as well as single-strand conformation polymorphism (SSCP)analysis (see, e.g., Marrogi et al, J. Cutan. Pathol. 26(8): 369-378(1999), both of which utilize polynucleotides encoding specific regionsof a protein to examine these regions within the protein.

II.A.2.) Antisense Embodiments

Other specifically contemplated nucleic acid related embodiments of theinvention disclosed herein are genomic DNA, cDNAs, ribozymes, andantisense molecules, as well as nucleic acid molecules based on analternative backbone, or including alternative bases, whether derivedfrom natural sources or synthesized, and include molecules capable ofinhibiting the RNA or protein expression of 98P4B6. For example,antisense molecules can be RNAs or other molecules, including peptidenucleic acids (PNAs) or non-nucleic acid molecules such asphosphorothioate derivatives that specifically bind DNA or RNA in a basepair-dependent manner. A skilled artisan can readily obtain theseclasses of nucleic acid molecules using the 98P4B6 polynucleotides andpolynucleotide sequences disclosed herein.

Antisense technology entails the administration of exogenousoligonucleotides that bind to a target polynucleotide located within thecells. The term “antisense” refers to the fact that sucholigonucleotides are complementary to their intracellular targets, e.g.,98P4B6. See for example, Jack Cohen, Oligodeoxynucleotides, AntisenseInhibitors of Gene Expression, CRC Press, 1989; and Synthesis 1:1-5(1988). The 98P4B6 antisense oligonucleotides of the present inventioninclude derivatives such as S-oligonucleotides (phosphorothioatederivatives or S-oligos, see, Jack Cohen, supra), which exhibit enhancedcancer cell growth inhibitory action. S-oligos (nucleosidephosphorothioates) are isoelectronic analogs of an oligonucleotide(O-oligo) in which a nonbridging oxygen atom of the phosphate group isreplaced by a sulfur atom. The S-oligos of the present invention can beprepared by treatment of the corresponding O-oligos with3H-1,2-benzodithiol-3-one-1,1-dioxide, which is a sulfur transferreagent. See, e.g., lyer, R. P. et al., J. Org. Chem. 55:4693-4698(1990); and lyer, R. P. et al., J. Am. Chem. Soc. 112:1253-1254 (1990).Additional 98P4B6 antisense oligonucleotides of the present inventioninclude morpholino antisense oligonucleotides known in the art (see,e.g., Partridge et al, 1996, Antisense & Nucleic Acid Drug Development6: 169-175).

The 98P4B6 antisense oligonucleotides of the present invention typicallycan be RNA or DNA that is complementary to and stably hybridizes withthe first 100 5′ codons or last 100 3′ codons of a 98P4B6 genomicsequence or the corresponding mRNA. Absolute complementarity is notrequired, although high degrees of complementarity are preferred. Use ofan oligonucleotide complementary to this region allows for the selectivehybridization to 98P4B6 mRNA and not to mRNA specifying other regulatorysubunits of protein kinase. In one embodiment, 98P4B6 antisenseoligonucleotides of the present invention are 15 to 30-mer fragments ofthe antisense DNA molecule that have a sequence that hybridizes to98P4B6 mRNA. Optionally, 98P4B6 antisense oligonucleotide is a 30-meroligonucleotide that is complementary to a region in the first 10 5′codons or last 10 3′ codons of 98P4B6. Alternatively, the antisensemolecules are modified to employ ribozymes in the inhibition of 98P4B6expression, see, e.g., L. A. Couture & D. T. Stinchcomb; Trends Genet12: 510-515 (1996).

II.A.3.) Primers and Primer Pairs

Further specific embodiments of these nucleotides of the inventioninclude primers and primer pairs, which allow the specific amplificationof polynucleotides of the invention or of any specific parts thereof,and probes that selectively or specifically hybridize to nucleic acidmolecules of the invention or to any part thereof. Probes can be labeledwith a detectable marker, such as, for example, a radioisotope,fluorescent compound, bioluminescent compound, a chemiluminescentcompound, metal chelator or enzyme. Such probes and primers are used todetect the presence of a 98P4B6 polynucleotide in a sample and as ameans for detecting a cell expressing a 98P4B6 protein.

Examples of such probes include polypeptides comprising all or part ofthe human 98P4B6 cDNA sequence shown in FIG. 2. Examples of primer pairscapable of specifically amplifying 98P4B6 mRNAs are also described inthe Examples. As will be understood by the skilled artisan, a great manydifferent primers and probes can be prepared based on the sequencesprovided herein and used effectively to amplify and/or detect a 98P4B6mRNA.

The 98P4B6 polynucleotides of the invention are useful for a variety ofpurposes, including but not limited to their use as probes and primersfor the amplification and/or detection of the 98P4B6 gene(s), mRNA(s),or fragments thereof; as reagents for the diagnosis and/or prognosis ofprostate cancer and other cancers; as coding sequences capable ofdirecting the expression of 98P4B6 polypeptides; as tools for modulatingor inhibiting the expression of the 98P4B6 gene(s) and/or translation ofthe 98P4B6 transcript(s); and as therapeutic agents.

The present invention includes the use of any probe as described hereinto identify and isolate a 98P4B6 or 98P4B6 related nucleic acid sequencefrom a naturally occurring source, such as humans or other mammals, aswell as the isolated nucleic acid sequence per se, which would compriseall or most of the sequences found in the probe used.

II.A.4.) Isolation of 98P4B6-Encoding Nucleic Acid Molecules

The 98P4B6 cDNA sequences described herein enable the isolation of otherpolynucleotides encoding 98P4B6 gene product(s), as well as theisolation of polynucleotides encoding 98P4B6 gene product homologs,alternatively spliced isoforms, allelic variants, and mutant forms of a98P4B6 gene product as well as polynucleotides that encode analogs of98P4B6-related proteins. Various molecular cloning methods that can beemployed to isolate full length cDNAs encoding a 98P4B6 gene are wellknown (see, for example, Sambrook, J. et al., Molecular Cloning: ALaboratory Manual, 2d edition, Cold Spring Harbor Press, New York, 1989;Current Protocols in Molecular Biology. Ausubel et al., Eds., Wiley andSons, 1995). For example, lambda phage cloning methodologies can beconveniently employed, using commercially available cloning systems(e.g., Lambda ZAP Express, Stratagene). Phage clones containing 98P4B6gene cDNAs can be identified by probing with a labeled 98P4B6 cDNA or afragment thereof. For example, in one embodiment, a 98P4B6 cDNA (e.g.,FIG. 2) or a portion thereof can be synthesized and used as a probe toretrieve overlapping and full-length cDNAs corresponding to a 98P4B6gene. A 98P4B6 gene itself can be isolated by screening genomic DNAlibraries, bacterial artificial chromosome libraries (BACs), yeastartificial chromosome libraries (YACs), and the like, with 98P4B6 DNAprobes or primers.

II.A.5.) Recombinant Nucleic Acid Molecules and Host-Vector Systems

The invention also provides recombinant DNA or RNA molecules containinga 98P4B6 polynucleotide, a fragment, analog or homologue thereof,including but not limited to phages, plasmids, phagemids, cosmids, YACs,BACs, as well as various viral and non-viral vectors well known in theart, and cells transformed or transfected with such recombinant DNA orRNA molecules. Methods for generating such molecules are well known(see, for example, Sambrook et al., 1989, supra).

The invention further provides a host-vector system comprising arecombinant DNA molecule containing a 98P486 polynucleotide, fragment,analog or homologue thereof within a suitable prokaryotic or eukaryotichost cell. Examples of suitable eukaryotic host cells include a yeastcell, a plant cell, or an animal cell, such as a mammalian cell or aninsect cell (e.g., a baculovirus-infectible cell such as an Sf9 orHighFive cell). Examples of suitable mammalian cells include variousprostate cancer cell lines such as DU145 and TsuPr1, other transfectableor transducible prostate cancer cell lines, primary cells (PrEC), aswell as a number of mammalian cells routinely used for the expression ofrecombinant proteins (e.g., COS, CHO, 293, 293T cells). Moreparticularly, a polynucleotide comprising the coding sequence of 98P4B6or a fragment, analog or homolog thereof can be used to generate 98P4B6proteins or fragments thereof using any number of host-vector systemsroutinely used and widely known in the art.

A wide range of host-vector systems suitable for the expression of98P4B6 proteins or fragments thereof are available, see for example,Sambrook et al., 1989, supra; Current Protocols in Molecular Biology,1995, supra). Preferred vectors for mammalian expression include but arenot limited to pcDNA 3.1 myc-His-tag (Invitrogen) and the retroviralvector pSRαtkneo (Muller et al., 1991, MCB 11:1785). Using theseexpression vectors, 98P4B6 can be expressed in several prostate cancerand non-prostate cell lines, including for example 293, 293T, rat-1, NIH3T3 and TsuPr1. The host-vector systems of the invention are useful forthe production of a 98P4B6 protein or fragment thereof. Such host-vectorsystems can be employed to study the functional properties of 98P4B6 and98P4B6 mutations or analogs.

Recombinant human 98P4B6 protein or an analog or homolog or fragmentthereof can be produced by mammalian cells transfected with a constructencoding a 98P4B6-related nucleotide. For example, 293T cells can betransfected with an expression plasmid encoding 98P4B6 or fragment,analog or homolog thereof, a 98P4B6-related protein is expressed in the293T cells, and the recombinant 98P4B6 protein is isolated usingstandard purification methods (e.g., affinity purification usinganti-98P4B6 antibodies). In another embodiment, a 98P4B6 coding sequenceis subcloned into the retroviral vector pSRαMSVtkneo and used to infectvarious mammalian cell lines, such as NIH 3T3, TsuPr1, 293 and rat-1 inorder to establish 98P4B6 expressing cell lines. Various otherexpression systems well known in the art can also be employed.Expression constructs encoding a leader peptide joined in frame to a98P4B6 coding sequence can be used for the generation of a secreted formof recombinant 98P4B6 protein.

As discussed herein, redundancy in the genetic code permits variation in98P4B6 gene sequences. In particular, it is known in the art thatspecific host species often have specific codon preferences, and thusone can adapt the disclosed sequence as preferred for a desired host.For example, preferred analog codon sequences typically have rare codons(i.e., codons having a usage frequency of less than about 20% in knownsequences of the desired host) replaced with higher frequency codons.Codon preferences for a specific species are calculated, for example, byutilizing codon usage tables available on the INTERNET.

Additional sequence modifications are known to enhance proteinexpression in a cellular host. These include elimination of sequencesencoding spurious polyadenylation signals, exon/intron splice sitesignals, transposon-like repeats, and/or other such well-characterizedsequences that are deleterious to gene expression. The GC content of thesequence is adjusted to levels average for a given cellular host, ascalculated by reference to known genes expressed in the host cell. Wherepossible, the sequence is modified to avoid predicted hairpin secondarymRNA structures. Other useful modifications include the addition of atranslational initiation consensus sequence at the start of the openreading frame, as described in Kozak, Mol. Cell Biol., 9:5073-5080(1989). Skilled artisans understand that the general rule thateukaryotic ribosomes initiate translation exclusively at the 5′ proximalAUG codon is abrogated only under rare conditions (see, e.g., Kozak PNAS92(7): 2662-2666, (1995) and Kozak NAR 15(20): 8125-8148 (1987)).

III.) 98P4B6-Related Proteins

Another aspect of the present invention provides 98P4B6-relatedproteins. Specific embodiments of 98P4B6 proteins comprise a polypeptidehaving all or part of the amino acid sequence of human 98P4B6 as shownin FIG. 2 or FIG. 3. Alternatively, embodiments of 98P4B6 proteinscomprise variant, homolog or analog polypeptides that have alterationsin the amino acid sequence of 98P4B6 shown in FIG. 2 or FIG. 3.

Embodiments of a 98P4B6 polypeptide include: a 98P4B6 polypeptide havinga sequence shown in FIG. 2, a peptide sequence of a 98P4B6 as shown inFIG. 2 wherein T is U; at least 10 contiguous nucleotides of apolypeptide having the sequence as shown in FIG. 2; or, at least 10contiguous peptides of a polypeptide having the sequence as shown inFIG. 2 where T is U. For example, embodiments of 98P4B6 peptidescomprise, without limitation:

(I) a protein comprising, consisting essentially of, or consisting of anamino acid sequence as shown in FIG. 2A-AL or FIG. 3A-J;

(II) a 98P4B6-related protein that is at least 90, 91, 92, 93, 94, 95,96, 97, 98, 99 or 100% homologous to an entire amino acid sequence shownin FIG. 2A-AL;

(III) a 98P4B6-related protein that is at least 90, 91, 92, 93, 94, 95,96, 97, 98, 99 or 100% identical to an entire amino acid sequence shownin FIG. 2A-AL or 3A-J;

(IV) a protein that comprises at least one peptide set forth in TablesVIII to XLIX, optionally with a proviso that it is not an entire proteinof FIG. 2;

(V) a protein that comprises at least one peptide set forth in TablesVIII-XXI, collectively, which peptide is also set forth in Tables XXIIto XLIX, collectively, optionally with a proviso that it is not anentire protein of FIG. 2;

(VI) a protein that comprises at least two peptides selected from thepeptides set forth in Tables VIII-XLIX, optionally with a proviso thatit is not an entire protein of FIG. 2;

(VII) a protein that comprises at least two peptides selected from thepeptides set forth in Tables VIII to XLIX collectively, with a provisothat the protein is not a contiguous sequence from an amino acidsequence of FIG. 2;

(VIII) a protein that comprises at least one peptide selected from thepeptides set forth in Tables VIII-XXI; and at least one peptide selectedfrom the peptides set forth in Tables XXII to XLIX, with a proviso thatthe protein is not a contiguous sequence from an amino acid sequence ofFIG. 2;

(IX) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a protein of FIGS. 3A, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I or 3J in any whole number increment up to 454, 45, 419, 490,576, 490, 454, 454, 576, or 490 respectively that includes at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Hydrophilicityprofile of FIG. 5;

(X) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35 amino acids of a protein of FIGS. 3A, 3B, 3C, 3D, 3E, 3F, 3G,3H, 3I or 3J in any whole number increment up to 454, 45, 419, 490, 576,490, 454, 454, 576, or 490 respectively that includes at least at least1, 2, 3, 4, 5, 6, 7,8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29,30, 31,32,33, 34,35 amino acidposition(s) having a value less than 0.5 in the Hydropathicity profileof FIG. 6;

(XI) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a protein of FIGS. 3A, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I or 3J in any whole number increment up to 454, 45, 419, 490,576, 490, 454, 454, 576, or 490 respectively that includes at least atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acidposition(s) having a value greater than 0.5 in the Percent AccessibleResidues profile of FIG. 7;

(XII) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35 amino acids of a protein of FIGS. 3A, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I or 3J in any whole number increment up to 454, 45, 419, 490,576, 490, 454, 454, 576, or 490 respectively that includes at least atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 aminoacid position(s) having a value greater than 0.5 in the AverageFlexibility profile of FIG. 8;

(XIII) a polypeptide comprising at least 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, amino acids of a protein of FIGS. 3A, 3B, 3C, 3D, 3E, 3F,3G, 3H, 3I or 3J in any whole number increment up to 454, 45, 419, 490,576, 490, 454, 454, 576, or 490 respectively that includes at least atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 aminoacid position(s) having a value greater than 0.5 in the Beta-turnprofile of FIG. 9;

(XIV) a peptide that occurs at least twice in Tables VIII-XXI and XXIIto XLIX, collectively;

(XV) a peptide that occurs at least three times in Tables VIII-XXI andXXII to XLIX, collectively;

(XVI) a peptide that occurs at least four times in Tables VIII-XXI andXXII to XLIX, collectively;

(XVII) a peptide that occurs at least five times in Tables VIII-XXI andXXII to XLIX, collectively;

(XVIII) a peptide that occurs at least once in Tables VIII-XXI, and atleast once in tables XXII to XLIX;

(XIX) a peptide that occurs at least once in Tables VIII-XXI, and atleast twice in tables XXII to XLIX;

(XX) a peptide that occurs at least twice in Tables VIII-XXI, and atleast once in tables XXII to XLIX;

(XXI) a peptide that occurs at least twice in Tables VIII-XXI, and atleast twice in tables XXII to XLIX;

(XXII) a peptide which comprises one two, three, four, or five of thefollowing characteristics, or an oligonucleotide encoding such peptide:

i) a region of at least 5 amino acids of a particular peptide of FIG. 3,in any whole number increment up to the full length of that protein inFIG. 3, that includes an amino acid position having a value equal to orgreater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, inthe Hydrophilicity profile of FIG. 5;

ii) a region of at least 5 amino acids of a particular peptide of FIG.3, in any whole number increment up to the full length of that proteinin FIG. 3, that includes an amino acid position having a value equal toor less than 0.5, 0.4, 0.3, 0.2, 0.1, or having a value equal to 0.0, inthe Hydropathicity profile of FIG. 6;

iii) a region of at least 5 amino acids of a particular peptide of FIG.3, in any whole number increment up to the full length of that proteinin FIG. 3, that includes an amino acid position having a value equal toor greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0,in the Percent Accessible Residues profile of FIG. 7;

iv) a region of at least 5 amino acids of a particular peptide of FIG.3, in any whole number increment up to the full length of that proteinin FIG. 3, that includes an amino acid position having a value equal toor greater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0,in the Average Flexibility profile of FIG. 8; or,

v) a region of at least 5 amino acids of a particular peptide of FIG. 3,in any whole number increment up to the full length of that protein inFIG. 3, that includes an amino acid position having a value equal to orgreater than 0.5, 0.6, 0.7, 0.8, 0.9, or having a value equal to 1.0, inthe Beta-turn profile of FIG. 9;

(XXIII) a composition comprising a peptide of (I)-(XXII) or an antibodyor binding region thereof together with a pharmaceutical excipientand/or in a human unit dose form.

(XXIV) a method of using a peptide of (I)-(XXII), or an antibody orbinding region thereof or a composition of (XXIII) in a method tomodulate a cell expressing 98P4B6,

(XXV) a method of using a peptide of (I)-(XXII) or an antibody orbinding region thereof or a composition of (XXIII) in a method todiagnose, prophylax, prognose, or treat an individual who bears a cellexpressing 98P4B6

(XXVI) a method of using a peptide of (I)-(XXII) or an antibody orbinding region thereof or a composition (XXIII) in a method to diagnose,prophylax, prognose, or treat an individual who bears a cell expressing98P4B6, said cell from a cancer of a tissue listed in Table I;

(XXVII) a method of using a peptide of (I)-(XXII) or an antibody orbinding region thereof or a composition of (XXIII) in a method todiagnose, prophylax, prognose, or treat a cancer;

(XXVIII) a method of using a peptide of (I)-(XXII) or an antibody orbinding region thereof or a composition of (XXIII) in a method todiagnose, prophylax, prognose, or treat a cancer of a tissue listed inTable I; and,

(XXIX) a method of using a peptide of (I)-(XXII) or an antibody orbinding region thereof or a composition (XXII I) in a method to identifyor characterize a modulator of a cell expressing 98P4B6.

As used herein, a range is understood to specifically disclose all wholeunit positions thereof.

Typical embodiments of the invention disclosed herein include 98P4B6polynucleotides that encode specific portions of 98P4B6 mRNA sequences(and those which are complementary to such sequences) such as those thatencode the proteins and/or fragments thereof, for example:

(a) 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165,170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375,400, 410, 420, 430, 440, 450, or 454 more contiguous amino acids of98P4B6 variant 1; the maximal lengths relevant for other variants are:variant 52, 45 amino acids; variant 5, 419 amino acids, variant 6,490,variant 7, 576 amino acids, variant 8, 490 amino acids, variant 13, 454,variant 14, 454 amino acids, variant 21, 576 amino acids, and variant25, 490 amino acids.

In general, naturally occurring allelic variants of human 98P4B6 share ahigh degree of structural identity and homology (e.g., 90% or morehomology). Typically, allelic variants of a 98P4B6 protein containconservative amino acid substitutions within the 98P4B6 sequencesdescribed herein or contain a substitution of an amino add from acorresponding position in a homologue of 98P4B6. One class of 98P4B6allelic variants are proteins that share a high degree of homology withat least a small region of a particular 98P4B6 amino acid sequence, butfurther contain a radical departure from the sequence, such as anon-conservative substitution, truncation, insertion or frame shift. Incomparisons of protein sequences, the terms, similarity, identity, andhomology each have a distinct meaning as appreciated in the field ofgenetics. Moreover, orthology and paralogy can be important conceptsdescribing the relationship of members of a given protein family in oneorganism to the members of the same family in other organisms.

Amino acid abbreviations are provided in Table II. Conservative aminoacid substitutions can frequently be made in a protein without alteringeither the conformation or the function of the protein. Proteins of theinvention can comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15conservative substitutions. Such changes include substituting any ofisoleucine (I), valine (V), and leucine (L) for any other of thesehydrophobic amino acids; aspartic acid (D) for glutamic acid (E) andvice versa; glutamine (Q) for asparagine (N) and vice versa; and serine(S) for threonine (T) and vice versa. Other substitutions can also beconsidered conservative, depending on the environment of the particularamino acid and its role in the three-dimensional structure of theprotein. For example, glycine (G) and alanine (A) can frequently beinterchangeable, as can alanine (A) and valine (V). Methionine (M),which is relatively hydrophobic, can frequently be interchanged withleucine and isoleucine, and sometimes with valine. Lysine (K) andarginine (R) are frequently interchangeable in locations in which thesignificant feature of the amino acid residue is its charge and thediffering pK's of these two amino acid residues are not significant.Still other changes can be considered “conservative” in particularenvironments (see, e.g. Table III herein; pages 13-15 “Biochemistry”2^(nd) ED. Lubert Stryer ed (Stanford University); Henikoff et al., PNAS1992 Vol 89 10915-10919; Lei et al., J Biol Chem 1995 May 19;270(20):11882-6).

Embodiments of the invention disclosed herein include a wide variety ofart-accepted variants or analogs of 98P4B6 proteins such as polypeptideshaving amino acid insertions, deletions and substitutions. 98P4B6variants can be made using methods known in the art such assite-directed mutagenesis, alanine scanning, and PCR mutagenesis.Site-directed mutagenesis (Carter et al., Nucl. Acids Res., 13:4331(1986); Zoller et al., Nucl. Acids Res., 10:6487 (1987)), cassettemutagenesis (Wells et al., Gene, 34:315 (1985)), restriction selectionmutagenesis (Wells et al., Philos. Trans. R. Soc. London SerA, 317:415(1986)) or other known techniques can be performed on the cloned DNA toproduce the 98P4B6 variant DNA.

Scanning amino acid analysis can also be employed to identify one ormore amino acids along a contiguous sequence that is involved in aspecific biological activity such as a protein-protein interaction.Among the preferred scanning amino acids are relatively small, neutralamino acids. Such amino acids include alanine, glycine, serine, andcysteine. Alanine is typically a preferred scanning amino acid amongthis group because it eliminates the side-chain beyond the beta-carbonand is less likely to alter the main-chain conformation of the variant.Alanine is also typically preferred because it is the most common aminoacid. Further, it is frequently found in both buried and exposedpositions (Creighton, The Proteins, (W.H. Freeman & Co., N.Y.); Chothia,J. Mol. Biol., 150:1 (1976)). If alanine substitution does not yieldadequate amounts of variant, an isosteric amino acid can be used.

As defined herein, 98P486 variants, analogs or homologs, have thedistinguishing attribute of having at least one epitope that is “crossreactive” with a 98P4B6 protein having an amino acid sequence of FIG. 3.As used in this sentence, “cross reactive” means that an antibody or Tcell that specifically binds to a 98P4B6 variant also specifically bindsto a 98P4B6 protein having an amino acid sequence set forth in FIG. 3. Apolypeptide ceases to be a variant of a protein shown in FIG. 3, when itno longer contains any epitope capable of being recognized by anantibody or T cell that specifically binds to the starting 98P4B6protein. Those skilled in the art understand that antibodies thatrecognize proteins bind to epitopes of varying size, and a grouping ofthe order of about four or five amino acids, contiguous or not, isregarded as a typical number of amino acids in a minimal epitope. See,e.g., Nair et al., J. Immunol 2000 165(12): 6949-6955; Hebbes et al.,Mol Immunol (1989) 26(9):865-73; Schwartz et al., J Immunol (1985)135(4):2598-608.

Other classes of 98P4B6-related protein variants share 70%, 75%, 80%,85% or 90% or more similarity with an amino acid sequence of FIG. 3, ora fragment thereof. Another specific class of 98P4B6 protein variants oranalogs comprises one or more of the 98P4B6 biological motifs describedherein or presently known in the art. Thus, encompassed by the presentinvention are analogs of 98P4B6 fragments (nucleic or amino acid) thathave altered functional (e.g. immunogenic) properties relative to thestarting fragment. It is to be appreciated that motifs now or whichbecome part of the art are to be applied to the nucleic or amino acidsequences of FIG. 2 or FIG. 3.

As discussed herein, embodiments of the claimed invention includepolypeptides containing less than the full amino acid sequence of a98P4B6 protein shown in FIG. 2 or FIG. 3. For example, representativeembodiments of the invention comprise peptides/proteins having any 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more contiguous amino acids of a98P4B6 protein shown in FIG. 2 or FIG. 3.

Moreover, representative embodiments of the invention disclosed hereininclude polypeptides consisting of about amino acid 1 to about aminoacid 10 of a 98P4B6 protein shown in FIG. 2 or FIG. 3, polypeptidesconsisting of about amino acid 10 to about amino acid 20 of a 98P4B6protein shown in FIG. 2 or FIG. 3, polypeptides consisting of aboutamino acid 20 to about amino acid 30 of a 98P4B6 protein shown in FIG. 2or FIG. 3, polypeptides consisting of about amino acid 30 to about aminoacid 40 of a 98P486 protein shown in FIG. 2 or FIG. 3, polypeptidesconsisting of about amino acid 40 to about amino acid 50 of a 98P4B6protein shown in FIG. 2 or FIG. 3, polypeptides consisting of aboutamino acid 50 to about amino acid 60 of a 98P4B6 protein shown in FIG. 2or FIG. 3, polypeptides consisting of about amino acid 60 to about aminoacid 70 of a 98P4B6 protein shown in FIG. 2 or FIG. 3, polypeptidesconsisting of about amino acid 70 to about amino acid 80 of a 98P4B6protein shown in FIG. 2 or FIG. 3, polypeptides consisting of aboutamino acid 80 to about amino acid 90 of a 98P4B6 protein shown in FIG. 2or FIG. 3, polypeptides consisting of about amino acid 90 to about aminoacid 100 of a 98P4B6 protein shown in FIG. 2 or FIG. 3, etc. throughoutthe entirety of a 98P4B6 amino acid sequence. Moreover, polypeptidesconsisting of about amino acid 1 (or 20 or 30 or 40 etc.) to about aminoacid 20, (or 130, or 140 or 150 etc.) of a 98P4B6 protein shown in FIG.2 or FIG. 3 are embodiments of the invention. It is to be appreciatedthat the starting and stopping positions in this paragraph refer to thespecified position as well as that position plus or minus 5 residues.

98P4B6-related proteins are generated using standard peptide synthesistechnology or using chemical cleavage methods well known in the art.Alternatively, recombinant methods can be used to generate nucleic acidmolecules that encode a 98P4B6-related protein. In one embodiment,nucleic acid molecules provide a means to generate defined fragments ofa 98P4B6 protein (or variants, homologs or analogs thereof).

III.A.) Motif-bearing Protein Embodiments

Additional illustrative embodiments of the invention disclosed hereininclude 98P4B6 polypeptides comprising the amino acid residues of one ormore of the biological motifs contained within a 98P4B6 polypeptidesequence set forth in FIG. 2 or FIG. 3. Various motifs are known in theart, and a protein can be evaluated for the presence of such motifs by anumber of publicly available sequence analysis tools (see, e.g., PFAM;BCM Search Launcher; PSORT; CBS; InterProScan; ScanProsite; Epimatrix™and Epimer™, Brown University; and BIMAS).

Motif bearing subsequences of all 98P4B6 variant proteins are set forthand identified in Tables VIII-XXI and XXII-XLIX.

Table V sets forth several frequently occurring motifs based on pfamsearches. The columns of Table V list (1) motif name abbreviation, (2)percent identity found amongst the different member of the motif family,(3) motif name or description and (4) most common function; locationinformation is included if the motif is relevant for location.

Polypeptides comprising one or more of the 98P4B6 motifs discussed aboveare useful in elucidating the specific characteristics of a malignantphenotype in view of the observation that the 98P4B6 motifs discussedabove are associated with growth dysregulation and because 98P4B6 isoverexpressed in certain cancers (See, e.g., Table I). Casein kinase II,cAMP and camp-dependent protein kinase, and Protein Kinase C, forexample, are enzymes known to be associated with the development of themalignant phenotype (see e.g. Chen et al., Lab Invest., 78(2): 165-174(1998); Gaiddon et al., Endocrinology 136(10): 4331-4338 (1995); Hall etal., Nucleic Acids Research 24(6): 1119-1126 (1996); Peterziel et al.,Oncogene 18(46): 6322-6329 (1999) and O'Brian, Oncol. Rep. 5(2): 305-309(1998)). Moreover, both glycosylation and myristoylation are proteinmodifications also associated with cancer and cancer progression (seee.g. Dennis et al., Biochem. Biophys. Acta 1473(1):21-34 (1999); Raju etal., Exp. Cell Res. 235(1): 145-154 (1997)). Amidation is anotherprotein modification also associated with cancer and cancer progression(see e.g. Treston et al., J. Natl. Cancer Inst. Monogr. (13): 169-175(1992)).

In another embodiment, proteins of the invention comprise one or more ofthe immunoreactive epitopes identified in accordance with art-acceptedmethods, such as the peptides set forth in Tables VIII-XXI andXXII-XLIX. CTL epitopes can be determined using specific algorithms toidentify peptides within a 98P4B6 protein that are capable of optimallybinding to specified HLA alleles (e.g., Table IV; Epimatrix™ andEpimer™, Brown University; and BIMAS). Moreover, processes foridentifying peptides that have sufficient binding affinity for HLAmolecules and which are correlated with being immunogenic epitopes, arewell known in the art, and are carried out without undueexperimentation. In addition, processes for identifying peptides thatare immunogenic epitopes, are well known in the art, and are carried outwithout undue experimentation either in vitro or in vivo.

Also known in the art are principles for creating analogs of suchepitopes in order to modulate immunogenicity. For example, one beginswith an epitope that bears a CTL or HTL motif (see, e.g., the HLA ClassI and HLA Class II motifs/supermotifs of Table IV). The epitope isanaloged by substituting out an amino acid at one of the specifiedpositions, and replacing it with another amino acid specified for thatposition. For example, on the basis of residues defined in Table IV, onecan substitute out a deleterious residue in favor of any other residue,such as a preferred residue; substitute a less-preferred residue with apreferred residue; or substitute an originally-occurring preferredresidue with another preferred residue. Substitutions can occur atprimary anchor positions or at other positions in a peptide; see, e.g.,Table IV.

A variety of references reflect the art regarding the identification andgeneration of epitopes in a protein of interest as well as analogsthereof. See, for example, WO 97/33602 to Chesnut et al. Sette,Immunogenetics 1999 50(3-4): 201-212; Sette et al., J. Immunol. 2001166(2): 1389-1397; Sidney et al., Hum. Immunol. 1997 58(1): 12-20; Kondoet al., Immunogenetics 1997 45(4): 249-258; Sidney et al., J. Immunol.1996 157(8): 3480-90; and Falk et al., Nature 351: 290-6 (1991); Hunt etal., Science 255:1261-3 (1992); Parker et al., J. Immunol. 149:3580-7(1992); Parker et al., J. Immunol. 152:163-75 (1994)); Kast et al., 1994152(8): 3904-12; Borras-Cuesta et al., Hum. Immunol. 2000 61(3):266-278; Alexander et al., J. Immunol. 2000 164(3); 164(3): 1625-1633;Alexander et al., PMID: 7895164, UI: 95202582; O'Sullivan et al., J.Immunol. 1991 147(8): 2663-2669; Alexander et al., Immunity 1994 1(9):751-761 and Alexander et al., Immunol. Res. 1998 18(2): 79-92.

Related embodiments of the invention include polypeptides comprisingcombinations of the different motifs set forth in Table VI, and/or, oneor more of the predicted CTL epitopes of Tables VIII-XXI and XXII-XLIX,and/or, one or more of the predicted HTL epitopes of Tables XLVI-XLIX,and/or, one or more of the T cell binding motifs known in the art.Preferred embodiments contain no insertions, deletions or substitutionseither within the motifs or within the intervening sequences of thepolypeptides. In addition, embodiments which include a number of eitherN-terminal and/or C-terminal amino acid residues on either side of thesemotifs may be desirable (to, for example, include a greater portion ofthe polypeptide architecture in which the motif is located). Typically,the number of N-terminal and/or C-terminal amino acid residues on eitherside of a motif is between about 1 to about 100 amino acid residues,preferably 5 to about 50 amino acid residues.

98P4B6-related proteins are embodied in many forms, preferably inisolated form. A purified 98P4B6 protein molecule will be substantiallyfree of other proteins or molecules that impair the binding of 98P4B6 toantibody, T cell or other ligand. The nature and degree of isolation andpurification will depend on the intended use. Embodiments of a98P4B6-related proteins include purified 98P4B6-related proteins andfunctional, soluble 98P4B6-related proteins. In one embodiment, afunctional, soluble 98P4B6 protein or fragment thereof retains theability to be bound by antibody, T cell or other ligand.

The invention also provides 98P4B6 proteins comprising biologicallyactive fragments of a 98P4B6 amino acid sequence shown in FIG. 2 or FIG.3. Such proteins exhibit properties of the starting 98P4B6 protein, suchas the ability to elicit the generation of antibodies that specificallybind an epitope associated with the starting 98P4B6 protein; to be boundby such antibodies; to elicit the activation of HTL or CTL; and/or, tobe recognized by HTL or CTL that also specifically bind to the startingprotein.

98P4B6-related polypeptides that contain particularly interestingstructures can be predicted and/or identified using various analyticaltechniques well known in the art, including, for example, the methods ofChou-Fasman, Garnier-Robson, Kyte-Doolittle, Eisenberg, Karplus-Schultzor Jameson-Wolf analysis, or based on immunogenicity. Fragments thatcontain such structures are particularly useful in generatingsubunit-specific ant-98P4B6 antibodies or T cells or in identifyingcellular factors that bind to 98P4B6. For example, hydrophilicityprofiles can be generated, and immunogenic peptide fragments identified,using the method of Hopp, T. P. and Woods, K. R., 1981, Proc. Natl.Acad. Sci. U.S.A. 78:3824-3828. Hydropathicity profiles can begenerated, and immunogenic peptide fragments identified, using themethod of Kyte, J. and Doolittle, R. F., 1982, J. Mol. Biol.157:105-132. Percent (%) Accessible Residues profiles can be generated,and immunogenic peptide fragments identified, using the method of JaninJ., 1979, Nature 277:491-492. Average Flexibility profiles can begenerated, and immunogenic peptide fragments identified, using themethod of Bhaskaran R., Ponnuswamy P. K., 1988, Int. J. Pept. ProteinRes. 32:242-255. Beta-turn profiles can be generated, and immunogenicpeptide fragments identified, using the method of Deleage, G., Roux B.,1987, Protein Engineering 1:289-294.

CTL epitopes can be determined using specific algorithms to identifypeptides within a 98P4B6 protein that are capable of optimally bindingto specified HLA alleles (e.g., by using the SYFPEITHI site; thelistings in Table IV(A)-(E); Epimatrix™ and Epimer™, Brown University;and BIMAS. Illustrating this, peptide epitopes from 98P4B6 that arepresented in the context of human MHC Class I molecules, e.g., HLA-A1,A2, A3, All, A24, B7 and B35 were predicted (see, e.g., Tables VIII-XXI,XXII-XLIX). Specifically, the complete amino acid sequence of the 98P4B6protein and relevant portions of other variants, i.e., for HLA Class Ipredictions 9 flanking residues on either side of a point mutation orexon juction, and for HLA Class II predictions 14 flanking residues oneither side of a point mutation or exon junction corresponding to thatvariant, were entered into the HLA Peptide Motif Search algorithm foundin the Bioinformatics and Molecular Analysis Section (BIMAS) web sitelisted above; in addition to the site SYFPEITHI.

The HLA peptide motif search algorithm was developed by Dr. Ken Parkerbased on binding of specific peptide sequences in the groove of HLAClass I molecules, in particular HLA-A2 (see, e.g., Falk et al., Nature351: 290-6 (1991); Hunt et al., Science 255:1261-3 (1992); Parker etal., J. Immunol. 149:3580-7 (1992); Parker et al., J. Immunol.152:163-75 (1994)). This algorithm allows location and ranking of 8-mer,9-mer, and 10-mer peptides from a complete protein sequence forpredicted binding to HLA-A2 as well as numerous other HLA Class Imolecules. Many HLA class I binding peptides are 8-, 9-, 10 or 11-mers.For example, for Class I HLA-A2, the epitopes preferably contain aleucine (L) or methionine (M) at position 2 and a valine (V) or leucine(L) at the C-terminus (see, e.g., Parker et al., J. Immunol. 149:3580-7(1992)). Selected results of 98P4B6 predicted binding peptides are shownin Tables VIII-XXI and XXII-XLIX herein. In Tables VIII-XXI andXXII-XLVII, selected candidates, 9-mers and 10-mers, for each familymember are shown along with their location, the amino acid sequence ofeach specific peptide, and an estimated binding score. In TablesXLVI-XLIX, selected candidates, 15-mers, for each family member areshown along with their location, the amino acid sequence of eachspecific peptide, and an estimated binding score. The binding scorecorresponds to the estimated half time of dissociation of complexescontaining the peptide at 37° C. at pH 6.5. Peptides with the highestbinding score are predicted to be the most tightly bound to HLA Class Ion the cell surface for the greatest period of time and thus representthe best immunogenic targets for T-cell recognition.

Actual binding of peptides to an HLA allele can be evaluated bystabilization of HLA expression on the antigen-processing defective cellline T2 (see, e.g., Xue et al., Prostate 30:73-8 (1997) and Peshwa etal., Prostate 36:129-38 (1998)). Immunogenicity of specific peptides canbe evaluated in vitro by stimulation of CD8+ cytotoxic T lymphocytes(CTL) in the presence of antigen presenting cells such as dendriticcells.

It is to be appreciated that every epitope predicted by the BIMAS site,Epimer™ and Epimatrix™ sites, or specified by the HLA class I or classII motifs available in the art or which become part of the art such asset forth in Table IV (or determined using SYFPEITHI or BIMAS) are to be“applied” to a 98P4B6 protein in accordance with the invention. As usedin this context “applied” means that a 98P4B6 protein is evaluated,e.g., visually or by computer-based patterns finding methods, asappreciated by those of skill in the relevant art. Every subsequence ofa 98P4B6 protein of 8, 9, 10, or 11 amino acid residues that bears anHLA Class I motif, or a subsequence of 9 or more amino acid residuesthat bear an HLA Class II motif are within the scope of the invention.

III.B.) Expression of 98P4B6-Related Proteins

In an embodiment described in the examples that follow, 98P4B6 can beconveniently expressed in cells (such as 293T cells) transfected with acommercially available expression vector such as a CMV-driven expressionvector encoding 98P4B6 with a C-terminal 6×His and MYC tag(pcDNA3.1/mycHIS, Invitrogen or Tag5, GenHunter Corporation, NashvilleTenn.). The Tag5 vector provides an IgGK secretion signal that can beused to facilitate the production of a secreted 98P4B6 protein intransfected cells. The secreted HIS-tagged 98P4B6 in the culture mediacan be purified, e.g., using a nickel column using standard techniques.

III.C.) Modifications of 98P4B6-Related Proteins

Modifications of 98P4B6-related proteins such as covalent modificationsare included within the scope of this invention. One type of covalentmodification includes reacting targeted amino acid residues of a 98P4B6polypeptide with an organic derivatizing agent that is capable ofreacting with selected side chains or the N- or C-terminal residues of a98P4B6 protein. Another type of covalent modification of a 98P4B6polypeptide included within the scope of this invention comprisesaltering the native glycosylation pattern of a protein of the invention.Another type of covalent modification of 98P4B6 comprises linking a98P4B6 polypeptide to one of a variety of nonproteinaceous polymers,e.g., polyethylene glycol (PEG), polypropylene glycol, orpolyoxyalkylenes, in the manner set forth in U.S. Pat. Nos. 4,640,835;4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.

The 98P4B6-related proteins of the present invention can also bemodified to form a chimeric molecule comprising 98P4B6 fused to another,heterologous polypeptide or amino acid sequence. Such a chimericmolecule can be synthesized chemically or recombinantly. A chimericmolecule can have a protein of the invention fused to anothertumor-associated antigen or fragment thereof. Alternatively, a proteinin accordance with the invention can comprise a fusion of fragments of a98P4B6 sequence (amino or nucleic acid) such that a molecule is createdthat is not, through its length, directly homologous to the amino ornucleic acid sequences shown in FIG. 2 or FIG. 3. Such a chimericmolecule can comprise multiples of the same subsequence of 98P4B6. Achimeric molecule can comprise a fusion of a 98P4B6-related protein witha polyhistidine epitope tag, which provides an epitope to whichimmobilized nickel can selectively bind, with cytokines or with growthfactors. The epitope tag is generally placed at the amino- orcarboxyl-terminus of a 98P4B6 protein. In an alternative embodiment, thechimeric molecule can comprise a fusion of a 98P4B6-related protein withan immunoglobulin or a particular region of an immunoglobulin. For abivalent form of the chimeric molecule (also referred to as an“immunoadhesin”), such a fusion could be to the Fc region of an IgGmolecule. The Ig fusions preferably include the substitution of asoluble (transmembrane domain deleted or inactivated) form of a 98P4B6polypeptide in place of at least one variable region within an Igmolecule. In a preferred embodiment, the immunoglobulin fusion includesthe hinge, CH2 and CH3, or the hinge, CHI, CH2 and CH3 regions of anIgGI molecule. For the production of immunoglobulin fusions see, e.g.,U.S. Pat. No. 5,428,130 issued Jun. 27, 1995.

III.D.) Uses of 98P4B6-Related Proteins

The proteins of the invention have a number of different specific uses.As 98P4B6 is highly expressed in prostate and other cancers,98P4B6-related proteins are used in methods that assess the status of98P4B6 gene products in normal versus cancerous tissues, therebyelucidating the malignant phenotype. Typically, polypeptides fromspecific regions of a 98P4B6 protein are used to assess the presence ofperturbations (such as deletions, insertions, point mutations etc.) inthose regions (such as regions containing one or more motifs). Exemplaryassays utilize antibodies or T cells targeting 98P4B6-related proteinscomprising the amino acid residues of one or more of the biologicalmotifs contained within a 98P4B6 polypeptide sequence in order toevaluate the characteristics of this region in normal versus canceroustissues or to elicit an immune response to the epitope. Alternatively,98P4B6-related proteins that contain the amino acid residues of one ormore of the biological motifs in a 98P4B6 protein are used to screen forfactors that interact with that region of 98P4B6.

98P4B6 protein fragments/subsequences are particularly useful ingenerating and characterizing domain-specific antibodies (e.g.,antibodies recognizing an extracellular or intracellular epitope of a98P4B6 protein), for identifying agents or cellular factors that bind to98P4B6 or a particular structural domain thereof, and in varioustherapeutic and diagnostic contexts, including but not limited todiagnostic assays, cancer vaccines and methods of preparing suchvaccines.

Proteins encoded by the 98P4B6 genes, or by analogs, homologs orfragments thereof, have a variety of uses, including but not limited togenerating antibodies and in methods for identifying ligands and otheragents and cellular constituents that bind to a 98P4B6 gene product.Antibodies raised against a 98P4B6 protein or fragment thereof areuseful in diagnostic and prognostic assays, and imaging methodologies inthe management of human cancers characterized by expression of 98P4B6protein, such as those listed in Table I. Such antibodies can beexpressed intracellularly and used in methods of treating patients withsuch cancers. 98P4B6-related nucleic acids or proteins are also used ingenerating HTL or CTL responses.

Various immunological assays useful for the detection of 98P4B6 proteinsare used, including but not limited to various types ofradioimmunoassays, enzyme-linked immunosorbent assays (ELISA),enzyme-linked immunofluorescent assays (ELIFA), immunocytochemicalmethods, and the like. Antibodies can be labeled and used asimmunological imaging reagents capable of detecting 98P4B6-expressingcells (e.g., in radioscintgraphic imaging methods). 98P4B6 proteins arealso particularly useful in generating cancer vaccines, as furtherdescribed herein.

IV.) 98P4B6 Antibodies

Another aspect of the invention provides antibodies that bind to98P4B6-related proteins. Preferred antibodies specifically bind to a98P4B6-related protein and do not bind (or bind weakly) to peptides orproteins that are not 98P4B6-related proteins under physiologicalconditions. In this context, examples of physiological conditionsinclude: 1) phosphate buffered saline; 2) Tris-buffered salinecontaining 25 mM Tris and 150 mM NaCl; or normal saline (0.9% NaCl); 4)animal serum such as human serum; or, 5) a combination of any of 1)through 4); these reactions preferably taking place at pH 7.5,alternatively in a range of pH 7.0 to 8.0, or alternatively in a rangeof pH 6.5 to 8.5; also, these reactions taking place at a temperaturebetween 4° C. to 37° C. For example, antibodies that bind 98P4B6 canbind 98P4B6-related proteins such as the homologs or analogs thereof.

98P4B6 antibodies of the invention are particularly useful in cancer(see, e.g., Table I) diagnostic and prognostic assays, and imagingmethodologies. Similarly, such antibodies are useful in the treatment,diagnosis, and/or prognosis of other cancers, to the extent 98P4B6 isalso expressed or overexpressed in these other cancers. Moreover,intracellularly expressed antibodies (e.g., single chain antibodies) aretherapeutically useful in treating cancers in which the expression of98P4B6 is involved, such as advanced or metastatic prostate cancers.

The invention also provides various immunological assays useful for thedetection and quantification of 98P4B6 and mutant 98P4B6-relatedproteins. Such assays can comprise one or more 98P4B6 antibodies capableof recognizing and binding a 98P4B6-related protein, as appropriate.These assays are performed within various immunological assay formatswell known in the art, including but not limited to various types ofradioimmunoassays, enzyme-linked immunosorbent assays (ELISA),enzyme-linked immunofluorescent assays (ELIFA), and the like.

Immunological non-antibody assays of the invention also comprise T cellimmunogenicity assays (inhibitory or stimulatory) as well as majorhistocompatibility complex (MHC) binding assays.

In addition, immunological imaging methods capable of detecting prostatecancer and other cancers expressing 98P4B6 are also provided by theinvention, including but not limited to radioscintigraphic imagingmethods using labeled 98P4B6 antibodies. Such assays are clinicallyuseful in the detection, monitoring, and prognosis of 98P4B6 expressingcancers such as prostate cancer.

98P4B6 antibodies are also used in methods for purifying a98P4B6-related protein and for isolating 98P4B6 homologues and relatedmolecules. For example, a method of purifying a 98P4B6-related proteincomprises incubating a 98P4B6 antibody, which has been coupled to asolid matrix, with a lysate or other solution containing a98P4B6-related protein under conditions that permit the 98P4B6 antibodyto bind to the 98P4B6-related protein; washing the solid matrix toeliminate impurities; and eluting the 98P4B6-related protein from thecoupled antibody. Other uses of 98P4B6 antibodies in accordance with theinvention include generating anti-idiotypic antibodies that mimic a98P4B6 protein.

Various methods for the preparation of antibodies are well known in theart. For example, antibodies can be prepared by immunizing a suitablemammalian host using a 98P4B6-related protein, peptide, or fragment, inisolated or immunoconjugated form (Antibodies: A Laboratory Manual, CSHPress, Eds., Harlow, and Lane (1988); Harlow, Antibodies, Cold SpringHarbor Press, NY (1989)). In addition, fusion proteins of 98P4B6 canalso be used, such as a 98P4B6 GST-fusion protein. In a particularembodiment, a GST fusion protein comprising all or most of the aminoacid sequence of FIG. 2 or FIG. 3 is produced, then used as an immunogento generate appropriate antibodies. In another embodiment, a98P4B6-related protein is synthesized and used as an immunogen.

In addition, naked DNA immunization techniques known in the art are used(with or without purified 98P4B6-related protein or 98P4B6 expressingcells) to generate an immune response to the encoded immunogen (forreview, see Donnelly et al., 1997, Ann. Rev. Immunol. 15: 617-648).

The amino acid sequence of a 98P4B6 protein as shown in FIG. 2 or FIG. 3can be analyzed to select specific regions of the 98P4B6 protein forgenerating antibodies. For example, hydrophobicity and hydrophilicityanalyses of a 98P4B6 amino acid sequence are used to identifyhydrophilic regions in the 98P4B6 structure. Regions of a 98P4B6 proteinthat show immunogenic structure, as well as other regions and domains,can readily be identified using various other methods known in the art,such as Chou-Fasman, Garnier-Robson, Kyte-Doolittle, Eisenberg,Karplus-Schultz or Jameson-Wolf analysis. Hydrophilicity profiles can begenerated using the method of Hopp, T. P. and Woods, K. R., 1981, Proc.Natl. Acad. Sci. U.S.A. 78:3824-3828. Hydropathicity profiles can begenerated using the method of Kyte, J. and Doolittle, R. F., 1982, J.Mol. Biol. 157:105-132. Percent (%) Accessible Residues profiles can begenerated using the method of Janin J., 1979, Nature 277:491-492.Average Flexibility profiles can be generated using the method ofBhaskaran R., Ponnuswamy P. K., 1988, Int. J. Pept. Protein Res.32:242-255. Beta-turn profiles can be generated using the method ofDeleage, G., Roux B., 1987, Protein Engineering 1:289-294. Thus, eachregion identified by any of these programs or methods is within thescope of the present invention. Methods for the generation of 98P4B6antibodies are further illustrated by way of the examples providedherein. Methods for preparing a protein or polypeptide for use as animmunogen are well known in the art. Also well known in the art aremethods for preparing immunogenic conjugates of a protein with acarrier, such as BSA, KLH or other carrier protein. In somecircumstances, direct conjugation using, for example, carbodiimidereagents are used; in other instances linking reagents such as thosesupplied by Pierce Chemical Co., Rockford, Ill., are effective.Administration of a 98P4B6 immunogen is often conducted by injectionover a suitable time period and with use of a suitable adjuvant, as isunderstood in the art. During the immunization schedule, titers ofantibodies can be taken to determine adequacy of antibody formation.

98P4B6 monoclonal antibodies can be produced by various means well knownin the art. For example, immortalized cell lines that secrete a desiredmonoclonal antibody are prepared using the standard hybridoma technologyof Kohler and Milstein or modifications that immortalizeantibody-producing B cells, as is generally known. Immortalized celllines that secrete the desired antibodies are screened by immunoassay inwhich the antigen is a 98P4B6-related protein. When the appropriateimmortalized cell culture is identified, the cells can be expanded andantibodies produced either from in vitro cultures or from ascites fluid.

The antibodies or fragments of the invention can also be produced, byrecombinant means. Regions that bind specifically to the desired regionsof a 98P4B6 protein can also be produced in the context of chimeric orcomplementarity-determining region (CDR) grafted antibodies of multiplespecies origin. Humanized or human 98P4B6 antibodies can also beproduced, and are preferred for use in therapeutic contexts. Methods forhumanizing murine and other non-human antibodies, by substituting one ormore of the non-human antibody CDRs for corresponding human antibodysequences, are well known (see for example, Jones et al., 1986, Nature321: 522-525; Riechmann et al., 1988, Nature 332: 323-327; Verhoeyen etal., 1988, Science 239: 1534-1536). See also, Carter et al., 1993, Proc.Natl. Acad. Sci. USA 89: 4285 and Sims et al., 1993, J. Immunol. 151:2296.

Methods for producing fully human monoclonal antibodies include phagedisplay and transgenic methods (for review, see Vaughan et al., 1998,Nature Biotechnology 16: 535-539). Fully human 98P4B6 monoclonalantibodies can be generated using cloning technologies employing largehuman Ig gene combinatorial libraries (i.e., phage display) (Griffithsand Hoogenboom, Building an in vitro immune system: human antibodiesfrom phage display libraries. In: Protein Engineering of AntibodyMolecules for Prophylactic and Therapeutic Applications in Man, Clark,M. (Ed.), Nottingham Academic, pp 45-64 (1993); Burton and Barbas, HumanAntibodies from combinatorial libraries. Id., pp 65-82). Fully human98P4B6 monoclonal antibodies can also be produced using transgenic miceengineered to contain human immunoglobulin gene loci as described in PCTPatent Application WO98/24893, Kucherlapati and Jakobovits et al.,published Dec. 3, 1997 (see also, Jakobovits, 1998, Exp. Opin. Invest.Drugs 7(4): 607-614; U.S. Pat. No. 6,162,963 issued 19 Dec. 2000; U.S.Pat. No. 6,150,584 issued 12 Nov. 2000; and, U.S. Pat. No. 6,114,598issued 5 Sep. 2000). This method avoids the in vitro manipulationrequired with phage display technology and efficiently produces highaffinity authentic human antibodies.

Reactivity of 98P4B6 antibodies with a 98P4B6-related protein can beestablished by a number of well known means, including Western blot,immunoprecipitation, ELISA, and FACS analyses using, as appropriate,98P4B6-related proteins, 98P4B6-expressing cells or extracts thereof. A98P4B6 antibody or fragment thereof can be labeled with a detectablemarker or conjugated to a second molecule. Suitable detectable markersinclude, but are not limited to, a radioisotope, a fluorescent compound,a bioluminescent compound, chemiluminescent compound, a metal chelatoror an enzyme. Further, bi-specific antibodies specific for two or more98P4B6 epitopes are generated using methods generally known in the art.Homodimeric antibodies can also be generated by cross-linking techniquesknown in the art (e.g., Wolff et al., Cancer Res. 53: 2560-2565).

V.) 98P4B6 Cellular Immune Responses

The mechanism by which T cells recognize antigens has been delineated.Efficacious peptide epitope vaccine compositions of the invention inducea therapeutic or prophylactic immune responses in very broad segments ofthe world-wide population. For an understanding of the value andefficacy of compositions of the invention that induce cellular immuneresponses, a brief review of immunology-related technology is provided.

A complex of an HLA molecule and a peptidic antigen acts as the ligandrecognized by HLA-restricted T cells (Buus, S. et al., Cell 47:1071,1986; Babbitt, B. P. et al., Nature 317:359, 1985; Townsend, A. andBodmer, H., Annu. Rev. Immunol. 7:601, 1989; Germain, R. N., Annu. Rev.Immunol. 11:403,1993). Through the study of single amino acidsubstituted antigen analogs and the sequencing of endogenously bound,naturally processed peptides, critical residues that correspond tomotifs required for specific binding to HLA antigen molecules have beenidentified and are set forth in Table IV (see also, e.g., Southwood, etal., J. Immunol. 160:3363,1998; Rammensee, et al., Immunogenetics41:178,1995; Rammensee et al., SYFPEITHI; Sette, A. and Sidney, J. Curr.Opin. Immunol. 10:478, 1998; Engelhard, V. H., Curr. Opin. Immunol.6:13,1994; Sette, A. and Grey, H. M., Curr. Opin. Immunol. 4:79,1992;Sinigaglia, F. and Hammer, J. Curr. Biol. 6:52, 1994; Ruppert et al.,Cell 74:929-937, 1993; Kondo et al., J. Immunol. 155:4307-4312, 1995;Sidney et al., J. Immunol. 157:3480-3490, 1996; Sidney et al., HumanImmunol. 45:79-93, 1996; Sette, A. and Sidney, J. Immunogenetics 1999November; 50(34):201-12, Review).

Furthermore, x-ray crystallographic analyses of HLA-peptide complexeshave revealed pockets within the peptide binding cleft/groove of HLAmolecules which accommodate, in an allele-specific mode, residues borneby peptide ligands; these residues in turn determine the HLA bindingcapacity of the peptides in which they are present. (See, e.g., Madden,D. R. Annu. Rev. Immunol. 13:587,1995; Smith, et al., Immunity 4:203,1996; Fremont et al., Immunity 8:305, 1998; Stern et al., Structure2:245, 1994; Jones, E. Y. Curr. Opin. Immunol 9:75, 1997; Brown, J. H.et al., Nature 364:33, 1993; Guo, H. C. et al., Proc. Natl. Acad. Sci.USA 90:8053, 1993; Guo, H. C. et al., Nature 360:364, 1992; Silver, M.L. et al., Nature 360:367, 1992; Matsumura, M. et al., Science 257:927,1992; Madden et al., Cell 70:1035, 1992; Fremont, D. H. et al., Science257:919, 1992; Saper, M. A., Bjorkman, P. J. and Wiley, D. C., J. Mol.Biol. 219:277, 1991.)

Accordingly, the definition of class I and class II allele-specific HLAbinding motifs, or class I or class II supermotifs allows identificationof regions within a protein that are correlated with binding toparticular HLA antigen(s).

Thus, by a process of HLA motif identification, candidates forepitope-based vaccines have been identified; such candidates can befurther evaluated by HLA-peptide binding assays to determine bindingaffinity and/or the time period of association of the epitope and itscorresponding HLA molecule. Additional confirmatory work can beperformed to select, amongst these vaccine candidates, epitopes withpreferred characteristics in terms of population coverage, and/orimmunogenicity.

Various strategies can be utilized to evaluate cellular immunogenicity,including:

1) Evaluation of primary T cell cultures from normal individuals (see,e.g., Wentworth, P. A. et al., Mol. Immunol. 32:603, 1995; Celis, E. etal., Proc. Natl. Acad. Sci. USA 91:2105, 1994; Tsai, V. et al., J.Immunol. 158:1796, 1997; Kawashima, I. et al., Human Immunol. 59:1,1998). This procedure involves the stimulation of peripheral bloodlymphocytes (PBL) from normal subjects with a test peptide in thepresence of antigen presenting cells in vitro over a period of severalweeks. T cells specific for the peptide become activated during thistime and are detected using, e.g., a lymphokine- or ⁵¹Cr-release assayinvolving peptide sensitized target cells.

2) Immunization of HLA transgenic mice (see, e.g., Wentworth, P. A. etal., J. Immunol. 26:97, 1996; Wentworth, P. A. et al., Int. Immunol.8:651, 1996; Alexander, J. et al., J. Immunol. 159:4753, 1997). Forexample, in such methods peptides in incomplete Freund's adjuvant areadministered subcutaneously to HLA transgenic mice. Several weeksfollowing immunization, splenocytes are removed and cultured in vitro inthe presence of test peptide for approximately one week.Peptide-specific T cells are detected using, e.g., a ⁵¹ Cr-release assayinvolving peptide sensitized target cells and target cells expressingendogenously generated antigen.

3) Demonstration of recall T cell responses from immune individuals whohave been either effectively vaccinated and/or from chronically illpatients (see, e.g., Rehermann, B. et al., J. Exp. Med. 181:1047, 1995;Doolan, D. L. et al., Immunity 7:97, 1997; Bertoni, R. et al., J. Clin.Invest. 100:503, 1997; Threlkeld, S. C. et al., J. Immunol. 159:1648,1997; Diepolder, H. M. et al., J. Virol. 71:6011, 1997). Accordingly,recall responses are detected by culturing PBL from subjects that havebeen exposed to the antigen due to disease and thus have generated animmune response “naturally”, or from patients who were vaccinatedagainst the antigen. PBL from subjects are cultured in vitro for 1-2weeks in the presence of test peptide plus antigen presenting cells(APC) to allow activation of “memory” T cells, as compared to “naive” Tcells. At the end of the culture period, T cell activity is detectedusing assays including ⁵¹ Cr release involving peptide-sensitizedtargets, T cell proliferation, or lymphokine release.

VI.) 98P4B6 Transgenic Animals

Nucleic acids that encode a 98P4B6-related protein can also be used togenerate either transgenic animals or “knock out” animals that, in turn,are useful in the development and screening of therapeutically usefulreagents. In accordance with established techniques, cDNA encoding98P4B6 can be used to clone genomic DNA that encodes 98P4B6. The clonedgenomic sequences can then be used to generate transgenic animalscontaining cells that express DNA that encode 98P4B6. Methods forgenerating transgenic animals, particularly animals such as mice orrats, have become conventional in the art and are described, forexample, in U.S. Pat. No. 4,736,866 issued 12 Apr. 1988, and U.S. Pat.No. 4,870,009 issued 26 Sep. 1989. Typically, particular cells would betargeted for 98P4B6 transgene incorporation with tissue-specificenhancers.

Transgenic animals that include a copy of a transgene encoding 98P4B6can be used to examine the effect of increased expression of DNA thatencodes 98P4B6. Such animals can be used as tester animals for reagentsthought to confer protection from, for example, pathological conditionsassociated with its overexpression. In accordance with this aspect ofthe invention, an animal is treated with a reagent and a reducedincidence of a pathological condition, compared to untreated animalsthat bear the transgene, would indicate a potential therapeuticintervention for the pathological condition.

Alternatively, non-human homologues of 98P4B6 can be used to construct a98P4B6 “knock out” animal that has a defective or altered gene encoding98P4B6 as a result of homologous recombination between the endogenousgene encoding 98P4B6 and altered genomic DNA encoding 98P4B6 introducedinto an embryonic cell of the animal. For example, cDNA that encodes98P4B6 can be used to clone genomic DNA encoding 98P4B6 in accordancewith established techniques. A portion of the genomic DNA encoding98P4B6 can be deleted or replaced with another gene, such as a geneencoding a selectable marker that can be used to monitor integration.Typically, several kilobases of unaltered flanking DNA (both at the 5′and 3′ ends) are included in the vector (see, e.g., Thomas and Capecchi,Cell, 51:503 (1987) for a description of homologous recombinationvectors). The vector is introduced into an embryonic stem cell line(e.g., by electroporation) and cells in which the introduced DNA hashomologously recombined with the endogenous DNA are selected (see, e.g.,Li et al., Cell, 69:915 (1992)). The selected cells are then injectedinto a blastocyst of an animal (e.g., a mouse or rat) to formaggregation chimeras (see, e.g., Bradley, in Teratocarcinomas andEmbryonic Stem Cells: A Practical Approach, E. J. Robertson, ed. (IRL,Oxford, 1987), pp. 113-152). A chimeric embryo can then be implantedinto a suitable pseudopregnant female foster animal, and the embryobrought to term to create a “knock out” animal. Progeny harboring thehomologously recombined DNA in their germ cells can be identified bystandard techniques and used to breed animals in which all cells of theanimal contain the homologously recombined DNA. Knock out animals can becharacterized, for example, for their ability to defend against certainpathological conditions or for their development of pathologicalconditions due to absence of a 98P4B6 polypeptide.

VIl.) Methods for the Detection of 98P4B6

Another aspect of the present invention relates to methods for detecting98P4B6 polynucleotides and 98P4B6-related proteins, as well as methodsfor identifying a cell that expresses 98P4B6. The expression profile of98P4B6 makes it a diagnostic marker for metastasized disease.Accordingly, the status of 98P4B6 gene products provides informationuseful for predicting a variety of factors including susceptibility toadvanced stage disease, rate of progression, and/or tumoraggressiveness. As discussed in detail herein, the status of 98P4B6 geneproducts in patient samples can be analyzed by a variety protocols thatare well known in the art including immunohistochemical analysis, thevariety of Northern blotting techniques including in situ hybridization,RT-PCR analysis (for example on laser capture micro-dissected samples),Western blot analysis and tissue array analysis.

More particularly, the invention provides assays for the detection of98P4B6 polynucleotides in a biological sample, such as serum, bone,prostate, and other tissues, urine, semen, cell preparations, and thelike. Detectable 98P4B6 polynucleotides include, for example, a 98P4B6gene or fragment thereof, 98P4B6 mRNA, alternative splice variant 98P4B6mRNAs, and recombinant DNA or RNA molecules that contain a 98P4B6polynucleotide. A number of methods for amplifying and/or detecting thepresence of 98P4B6 polynucleotides are well known in the art and can beemployed in the practice of this aspect of the invention.

In one embodiment, a method for detecting a 98P4B6 mRNA in a biologicalsample comprises producing cDNA from the sample by reverse transcriptionusing at least one primer; amplifying the cDNA so produced using a98P4B6 polynucleotides as sense and antisense primers to amplify 98P4B6cDNAs therein; and detecting the presence of the amplified 98P4B6 cDNA.Optionally, the sequence of the amplified 98P4B6 cDNA can be determined.

In another embodiment, a method of detecting a 98P4B6 gene in abiological sample comprises first isolating genomic DNA from the sample;amplifying the isolated genomic DNA using 98P4B6 polynucleotides assense and antisense primers; and detecting the presence of the amplified98P4B6 gene. Any number of appropriate sense and antisense probecombinations can be designed from a 98P4B6 nucleotide sequence (see,e.g., FIG. 2) and used for this purpose.

The invention also provides assays for detecting the presence of a98P4B6 protein in a tissue or other biological sample such as serum,semen, bone, prostate, urine, cell preparations, and the like. Methodsfor detecting a 98P4B6-related protein are also well known and include,for example, immunoprecipitation, immunohistochemical analysis, Westernblot analysis, molecular binding assays, ELISA, ELIFA and the like. Forexample, a method of detecting the presence of a 98P4B6-related proteinin a biological sample comprises first contacting the sample with a98P4B6 antibody, a 98P4B6-reactive fragment thereof, or a recombinantprotein containing an antigen-binding region of a 98P4B6 antibody; andthen detecting the binding of 98P4B6-related protein in the sample.

Methods for identifying a cell that expresses 98P4B6 are also within thescope of the invention. In one embodiment, an assay for identifying acell that expresses a 98P4B6 gene comprises detecting the presence of98P4B6 mRNA in the cell. Methods for the detection of particular mRNAsin cells are well known and include, for example, hybridization assaysusing complementary DNA probes (such as in situ hybridization usinglabeled 98P4B6 riboprobes, Northern blot and related techniques) andvarious nucleic acid amplification assays (such as RT-PCR usingcomplementary primers specific for 98P4B6, and other amplification typedetection methods, such as, for example, branched DNA, SISBA, TMA andthe like). Alternatively, an assay for identifying a cell that expressesa 98P4B6 gene comprises detecting the presence of 98P4B6-related proteinin the cell or secreted by the cell. Various methods for the detectionof proteins are well known in the art and are employed for the detectionof 98P4B6-related proteins and cells that express 98P4B6-relatedproteins.

98P4B6 expression analysis is also useful as a tool for identifying andevaluating agents that modulate 98P4B6 gene expression. For example,98P4B6 expression is significantly upregulated in prostate cancer, andis expressed in cancers of the tissues listed in Table I. Identificationof a molecule or biological agent that inhibits 98P4B6 expression orover-expression in cancer cells is of therapeutic value. For example,such an agent can be identified by using a screen that quantifies 98P4B6expression by RT-PCR, nucleic acid hybridization or antibody binding.

VIII.) Methods for Monitoring the Status of 98P4B6-related Genes andTheir Products

Oncogenesis is known to be a multistep process where cellular growthbecomes progressively dysregulated and cells progress from a normalphysiological state to precancerous and then cancerous states (see,e.g., Alers et al., Lab Invest. 77(5): 437-438 (1997) and Isaacs et al.,Cancer Surv. 23: 19-32 (1995)). In this context, examining a biologicalsample for evidence of dysregulated cell growth (such as aberrant 98P4B6expression in cancers) allows for early detection of such aberrantphysiology, before a pathologic state such as cancer has progressed to astage that therapeutic options are more limited and or the prognosis isworse. In such examinations, the status of 98P4B6 in a biological sampleof interest can be compared, for example, to the status of 98P4B6 in acorresponding normal sample (e.g. a sample from that individual oralternatively another individual that is not affected by a pathology).An alteration in the status of 98P4B6 in the biological sample (ascompared to the normal sample) provides evidence of dysregulatedcellular growth. In addition to using a biological sample that is notaffected by a pathology as a normal sample, one can also use apredetermined normative value such as a predetermined normal level ofmRNA expression (see, e.g., Grever et al., J. Comp. Neurol. 1996 Dec 9;376(2): 306-14 and U.S. Pat. No. 5,837,501) to compare 98P4B6 status ina sample.

The term “status” in this context is used according to its art acceptedmeaning and refers to the condition or state of a gene and its products.Typically, skilled artisans use a number of parameters to evaluate thecondition or state of a gene and its products. These include, but arenot limited to the location of expressed gene products (including thelocation of 98P4B6 expressing cells) as well as the level, andbiological activity of expressed gene products (such as 98P4B6 mRNA,polynucleotides and polypeptides). Typically, an alteration in thestatus of 98P4B6 comprises a change in the location of 98P4B6 and/or98P4B6 expressing cells and/or an increase in 98P4B6 mRNA and/or proteinexpression.

98P4B6 status in a sample can be analyzed by a number of means wellknown in the art, including without limitation, immunohistochemicalanalysis, in situ hybridization, RT-PCR analysis on laser capturemicro-dissected samples, Western blot analysis, and tissue arrayanalysis. Typical protocols for evaluating the status of a 98P4B6 geneand gene products are found, for example in Ausubel et al. eds., 1995,Current Protocols In Molecular Biology, Units 2 (Northern Blotting), 4(Southern Blotting), 15 (Immunoblotting) and 18 (PCR Analysis). Thus,the status of 98P4B6 in a biological sample is evaluated by variousmethods utilized by skilled artisans including, but not limited togenomic Southern analysis (to examine, for example perturbations in a98P4B6 gene), Northern analysis and/or PCR analysis of 98P4B6 mRNA (toexamine, for example alterations in the polynucleotide sequences orexpression levels of 98P4B6 mRNAs), and, Western and/orimmunohistochemical analysis (to examine, for example alterations inpolypeptide sequences, alterations in polypeptide localization within asample, alterations in expression levels of 98P4B6 proteins and/orassociations of 98P4B6 proteins with polypeptide binding partners).Detectable 98P4B6 polynucleotides include, for example, a 98P4B6 gene orfragment thereof, 98P4B6 mRNA, alternative splice variants, 98P4B6mRNAs, and recombinant DNA or RNA molecules containing a 98P4B6polynucleotide.

The expression profile of 98P4B6 makes it a diagnostic marker for localand/or metastasized disease, and provides information on the growth oroncogenic potential of a biological sample. In particular, the status of98P4B6 provides information useful for predicting susceptibility toparticular disease stages, progression, and/or tumor aggressiveness. Theinvention provides methods and assays for determining 98P4B6 status anddiagnosing cancers that express 98P4B6, such as cancers of the tissueslisted in Table I. For example, because 98P4B6 mRNA is so highlyexpressed in prostate and other cancers relative to normal prostatetissue, assays that evaluate the levels of 98P4B6 mRNA transcripts orproteins in a biological sample can be used to diagnose a diseaseassociated with 98P4B6 dysregulation, and can provide prognosticinformation useful in defining appropriate therapeutic options.

The expression status of 98P4B6 provides information including thepresence, stage and location of dysplastic, precancerous and cancerouscells, predicting susceptibility to various stages of disease, and/orfor gauging tumor aggressiveness. Moreover, the expression profile makesit useful as an imaging reagent for metastasized disease. Consequently,an aspect of the invention is directed to the various molecularprognostic and diagnostic methods for examining the status of 98P4B6 inbiological samples such as those from individuals suffering from, orsuspected of suffering from a pathology characterized by dysregulatedcellular growth, such as cancer.

As described above, the status of 98P4B6 in a biological sample can beexamined by a number of well-known procedures in the art. For example,the status of 98P4B6 in a biological sample taken from a specificlocation in the body can be examined by evaluating the sample for thepresence or absence of 98P4B6 expressing cells (e.g. those that express98P4B6 mRNAs or proteins). This examination can provide evidence ofdysregulated cellular growth, for example, when 98P4B6-expressing cellsare found in a biological sample that does not normally contain suchcells (such as a lymph node), because such alterations in the status of98P4B6 in a biological sample are often associated with dysregulatedcellular growth. Specifically, one indicator of dysregulated cellulargrowth is the metastases of cancer cells from an organ of origin (suchas the prostate) to a different area of the body (such as a lymph node).In this context, evidence of dysregulated cellular growth is importantfor example because occult lymph node metastases can be detected in asubstantial proportion of patients with prostate cancer, and suchmetastases are associated with known predictors of disease progression(see, e.g., Murphy et al., Prostate 42(4): 315-317 (2000);Su et al.,Semin. Surg. Oncol. 18(1): 17-28 (2000) and Freeman et al., J Urol 1995August 154(2 Pt 1):474-8).

In one aspect, the invention provides methods for monitoring 98P4B6 geneproducts by determining the status of 98P4B6 gene products expressed bycells from an individual suspected of having a disease associated withdysregulated cell growth (such as hyperplasia or cancer) and thencomparing the status so determined to the status of 98P4B6 gene productsin a corresponding normal sample. The presence of aberrant 98P4B6 geneproducts in the test sample relative to the normal sample provides anindication of the presence of dysregulated cell growth within the cellsof the individual.

In another aspect, the invention provides assays useful in determiningthe presence of cancer in an individual, comprising detecting asignificant increase in 98P4B6 mRNA or protein expression in a test cellor issue sample relative to expression levels in the correspondingnormal cell or tissue. The presence of 98P4B6 mRNA can, for example, beevaluated in tissues including but not limited to those listed in TableI. The presence of significant 98P4B6 expression in any of these tissuesis useful to indicate the emergence, presence and/or severity of acancer, since the corresponding normal tissues do not express 98P4B6mRNA or express it at lower levels.

In a related embodiment, 98P4B6 status is determined at the proteinlevel rather than at the nucleic acid level. For example, such a methodcomprises determining the level of 98P4B6 protein expressed by cells ina test issue sample and comparing the level so determined to the levelof 98P4B6 expressed in a corresponding normal sample. In one embodiment,the presence of 98P4B6 protein is evaluated, for example, usingimmunohistochemical methods. 98P4B6 antibodies or binding partnerscapable of detecting 98P4B6 protein expression are used in a variety ofassay formats well known in the art for this purpose.

In a further embodiment, one can evaluate the status of 98P4B6nucleotide and amino acid sequences in a biological sample in order toidentify perturbations in the structure of these molecules. Theseperturbations can include insertions, deletions, substitutions and thelike. Such evaluations are useful because perturbations in thenucleotide and amino acid sequences are observed in a large number ofproteins associated with a growth dysregulated phenotype (see, e.g.,Marrogi et al., 1999, J. Cutan. Pathol. 26(8):369-378). For example, amutation in the sequence of 98P4B6 may be indicative of the presence orpromotion of a tumor. Such assays therefore have diagnostic andpredictive value where a mutation in 98P4B6 indicates a potential lossof function or increase in tumor growth.

A wide variety of assays for observing perturbations in nucleotide andamino acid sequences are well known in the art. For example, the sizeand structure of nucleic acid or amino acid sequences of 98P4B6 geneproducts are observed by the Northern, Southern, Western, PCR and DNAsequencing protocols discussed herein. In addition, other methods forobserving perturbations in nucleotide and amino acid sequences such assingle strand conformation polymorphism analysis are well known in theart (see, e.g., U.S. Pat. No. 5,382,510 issued 7 Sep. 1999, and U.S.Pat. No. 5,952,170 issued 17 Jan. 1995).

Additionally, one can examine the methylation status of a 98P4B6 gene ina biological sample. Aberrant demethylation and/or hypermethylation ofCpG islands in gene 5′ regulatory regions frequently occurs inimmortalized and transformed cells, and can result in altered expressionof various genes. For example, promoter hypermethylation of the pi-classglutathione S-transferase (a protein expressed in normal prostate butnot expressed in >90% of prostate carcinomas) appears to permanentlysilence transcription of this gene and is the most frequently detectedgenomic alteration in prostate carcinomas (De Marzo et al., Am. J.Pathol. 155(6): 1985-1992 (1999)). In addition, this alteration ispresent in at least 70% of cases of high-grade prostatic intraepithelialneoplasia (PIN) (Brooks et al., Cancer Epidemiol. Biomarkers Prev.,1998, 7:531-536). In another example, expression of the LAGE-I tumorspecific gene (which is not expressed in normal prostate but isexpressed in 25-50% of prostate cancers) is induced by deoxy-azacytidinein lymphoblastoid cells, suggesting that tumoral expression is due todemethylation (Lethe et al., Int. J. Cancer 76(6): 903-908 (1998)). Avariety of assays for examining methylation status of a gene are wellknown in the art. For example, one can utilize, in Southernhybridization approaches, methylation-sensitive restriction enzymes thatcannot cleave sequences that contain methylated CpG sites to assess themethylation status of CpG islands. In addition, MSP (methylationspecific PCR) can rapidly profile the methylation status of all the CpGsites present in a CpG island of a given gene. This procedure involvesinitial modification of DNA by sodium bisulfite (which will convert allunmethylated cytosines to uracil) followed by amplification usingprimers specific for methylated versus unmethylated DNA. Protocolsinvolving methylation interference can also be found for example inCurrent Protocols In Molecular Biology, Unit 12, Frederick M. Ausubel etal. eds., 1995.

Gene amplification is an additional method for assessing the status of98P4B6. Gene amplification is measured in a sample directly, forexample, by conventional Southern blotting or Northern blotting toquantitate the transcription of mRNA (Thomas, 1980, Proc. Natl. Acad.Sci. USA, 77:5201-5205), dot blotting (DNA analysis), or in situhybridization, using an appropriately labeled probe, based on thesequences provided herein. Alternatively, antibodies are employed thatrecognize specific duplexes, including DNA duplexes, RNA duplexes, andDNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turnare labeled and the assay carded out where the duplex is bound to asurface, so that upon the formation of duplex on the surface, thepresence of antibody bound to the duplex can be detected.

Biopsied tissue or peripheral blood can be conveniently assayed for thepresence of cancer cells using for example, Northern, dot blot or RT-PCRanalysis to detect 98P4B6 expression. The presence of RT-PCR amplifiable98P4B6 mRNA provides an indication of the presence of cancer. RT-PCRassays are well known in the art. RT-PCR detection assays for tumorcells in peripheral blood are currently being evaluated for use in thediagnosis and management of a number of human solid tumors. In theprostate cancer field, these include RT-PCR assays for the detection ofcells expressing PSA and PSM (Verkaik et al, 1997, Urol. Res.25:373-384; Ghossein et al, 1995, J. Clin. Oncol. 13:1195-2000; Hestonet al, 1995, Clin. Chem. 41:1687-1688).

A further aspect of the invention is an assessment of the susceptibilitythat an individual has for developing cancer. In one embodiment, amethod for predicting susceptibility to cancer comprises detecting98P4B6 mRNA or 98P4B6 protein in a tissue sample, its presenceindicating susceptibility to cancer, wherein the degree of 98P4B6 mRNAexpression correlates to the degree of susceptibility. In a specificembodiment, the presence of 98P4B6 in prostate or other tissue isexamined, with the presence of 98P4B6 in the sample providing anindication of prostate cancer susceptibility (or the emergence orexistence of a prostate tumor). Similarly, one can evaluate theintegrity 98P4B6 nucleotide and amino acid sequences in a biologicalsample, in order to identify perturbations in the structure of thesemolecules such as insertions, deletions, substitutions and the like. Thepresence of one or more perturbations in 98P4B6 gene products in thesample is an indication of cancer susceptibility (or the emergence orexistence of a tumor).

The invention also comprises methods for gauging tumor aggressiveness.In one embodiment, a method for gauging aggressiveness of a tumorcomprises determining the level of 98P4B6 mRNA or 98P4B6 proteinexpressed by tumor cells, comparing the level so determined to the levelof 98P4B6 mRNA or 98P4B6 protein expressed in a corresponding normaltissue taken from the same individual or a normal tissue referencesample, wherein the degree of 98P4B6 mRNA or 98P4B6 protein expressionin the tumor sample relative to the normal sample indicates the degreeof aggressiveness. In a specific embodiment, aggressiveness of a tumoris evaluated by determining the extent to which 98P4B6 is expressed inthe tumor cells, with higher expression levels indicating moreaggressive tumors. Another embodiment is the evaluation of the integrityof 98P4B6 nucleotide and amino acid sequences in a biological sample, inorder to identify perturbations in the structure of these molecules suchas insertions, deletions, substitutions and the like. The presence ofone or more perturbations indicates more aggressive tumors.

Another embodiment of the invention is directed to methods for observingthe progression of a malignancy in an individual over time. In oneembodiment, methods for observing the progression of a malignancy in anindividual over time comprise determining the level of 98P4B6 mRNA or98P4B6 protein expressed by cells in a sample of the tumor, comparingthe level so determined to the level of 98P4B6 mRNA or 98P4B6 proteinexpressed in an equivalent tissue sample taken from the same individualat a different time, wherein the degree of 98P4B6 mRNA or 98P4B6 proteinexpression in the tumor sample over time provides information on theprogression of the cancer. In a specific embodiment, the progression ofa cancer is evaluated by determining 98P4B6 expression in the tumorcells over time, where increased expression over time indicates aprogression of the cancer. Also, one can evaluate the integrity 98P4B6nucleotide and amino acid sequences in a biological sample in order toidentify perturbations in the structure of these molecules such asinsertions, deletions, substitutions and the like, where the presence ofone or more perturbations indicates a progression of the cancer.

The above diagnostic approaches can be combined with any one of a widevariety of prognostic and diagnostic protocols known in the art. Forexample, another embodiment of the invention is directed to methods forobserving a coincidence between the expression of 98P4B6 gene and 98P4B6gene products (or perturbations in 98P4B6 gene and 98P4B6 gene products)and a factor that is associated with malignancy, as a means fordiagnosing and prognosticating the status of a issue sample. A widevariety of factors associated with malignancy can be utilized, such asthe expression of genes associated with malignancy (e.g. PSA, PSCA andPSM expression for prostate cancer etc.) as well as gross cytologicalobservations (see, e.g., Bocking et al., 1984, Anal. Quant. Cytol.6(2):74-88; Epstein, 1995, Hum. Pathol. 26(2):223-9; Thorson et al.,1998, Mod. Pathol. 11(6):543-51; Baisden et al., 1999, Am. J. Surg.Pathol. 23(8):918-24). Methods for observing a coincidence between theexpression of 98P4B6 gene and 98P4B6 gene products (or perturbations in98P4B6 gene and 98P486 gene products) and another factor that isassociated with malignancy are useful, for example, because the presenceof a set of specific factors that coincide with disease providesinformation crucial for diagnosing and prognosticating the status of aissue sample.

In one embodiment, methods for observing a coincidence between theexpression of 98P4B6 gene and 98P4B6 gene products (or perturbations in98P4B6 gene and 98P4B6 gene products) and another factor associated withmalignancy entails detecting the overexpression of 98P4B6 mRNA orprotein in a tissue sample, detecting the overexpression of PSA mRNA orprotein in a issue sample (or PSCA or PSM expression), and observing acoincidence of 98P4B6 mRNA or protein and PSA mRNA or proteinoverexpression (or PSCA or PSM expression). In a specific embodiment,the expression of 98P4B6 and PSA mRNA in prostate issue is examined,where the coincidence of 98P4B6 and PSA mRNA overexpression in thesample indicates the existence of prostate cancer, prostate cancersusceptibility or the emergence or status of a prostate tumor.

Methods for detecting and quantifying the expression of 98P4B6 mRNA orprotein are described herein, and standard nucleic acid and proteindetection and quantification technologies are well known in the art.Standard methods for the detection and quantification of 98P4B6 mRNAinclude in situ hybridization using labeled 98P4B6 riboprobes, Northernblot and related techniques using 98P4B6 polynucleotide probes, RT-PCRanalysis using primers specific for 98P4B6, and other amplification typedetection methods, such as, for example, branched DNA, SISBA, TMA andthe like. In a specific embodiment, semi-quantitative RT-PCR is used todetect and quantify 98P4B6 mRNA expression. Any number of primerscapable of amplifying 98P4B6 can be used for this purpose, including butnot limited to the various primer sets specifically described herein. Ina specific embodiment, polyclonal or monoclonal antibodies specificallyreactive with the wild-type 98P4B6 protein can be used in animmunohistochemical assay of biopsied tissue.

IX.) Identification of Molecules That Interact With 98P4B6

The 98P4B6 protein and nucleic acid sequences disclosed herein allow askilled artisan to identify proteins, small molecules and other agentsthat interact with 98P4B6, as well as pathways activated by 98P4B6 viaany one of a variety of art accepted protocols. For example, one canutilize one of the so-called interaction trap systems (also referred toas the “two-hybrid assay”). In such systems, molecules interact andreconstitute a transcription factor which directs expression of areporter gene, whereupon the expression of the reporter gene is assayed.Other systems identify protein-protein interactions in vivo throughreconstitution of a eukaryotic transcriptional activator, see, e.g.,U.S. Pat. No. 5,955,280 issued 21 Sep. 1999, U.S. Pat. No. 5,925,523issued 20 Jul. 1999, U.S. Pat. No. 5,846,722 issued 8 Dec. 1998 and U.S.Pat. No. 6,004,746 issued 21 Dec. 1999. Algorithms are also available inthe art for genome-based predictions of protein function (see, e.g.,Marcotte, et al., Nature 402: 4 Nov. 1999, 83-86).

Alternatively one can screen peptide libraries to identify moleculesthat interact with 98P4B6 protein sequences. In such methods, peptidesthat bind to 98P4B6 are identified by screening libraries that encode arandom or controlled collection of amino acids. Peptides encoded by thelibraries are expressed as fusion proteins of bacteriophage coatproteins, the bacteriophage particles are then screened against the98P4B6 protein(s).

Accordingly, peptides having a wide variety of uses, such astherapeutic, prognostic or diagnostic reagents, are thus identifiedwithout any prior information on the structure of the expected ligand orreceptor molecule. Typical peptide libraries and screening methods thatcan be used to identify molecules that interact with 98P4B6 proteinsequences are disclosed for example in U.S. Pat. No. 5,723,286 issued 3Mar. 1998 and U.S. Pat. No. 5,733,731 issued 31 Mar. 1998.

Alternatively, cell lines that express 98P4B6 are used to identifyprotein-protein interactions mediated by 98P4B6. Such interactions canbe examined using immunoprecipitation techniques (see, e.g., HamiltonB.J., et al. Biochem. Biophys. Res. Commun. 1999, 261:646-51). 98P4B6protein can be immunoprecipitated from 98P4B6-expressing cell linesusing anti-98P4B6 antibodies. Alternatively, antibodies against His-tagcan be used in a cell line engineered to express fusions of 98P4B6 and aHis-tag (vectors mentioned above). The immunoprecipitated complex can beexamined for protein association by procedures such as Western blotting,³⁵S-methionine labeling of proteins, protein microsequencing, silverstaining and two-dimensional gel electrophoresis.

Small molecules and ligands that interact with 98P4B6 can be identifiedthrough related embodiments of such screening assays. For example, smallmolecules can be identified that interfere with protein function,including molecules that interfere with 98P4B6's ability to mediatephosphorylation and de-phosphorylation, interaction with DNA or RNAmolecules as an indication of regulation of cell cycles, secondmessenger signaling or tumorigenesis. Similarly, small molecules thatmodulate 98P4B6-related ion channel, protein pump, or cell communicationfunctions are identified and used to treat patients that have a cancerthat expresses 98P4B6 (see, e.g., Hille, B., Ionic Channels of ExcitableMembranes 2^(nd) Ed., Sinauer Assoc., Sunderland, Mass., 1992).Moreover, ligands that regulate 98P4B6 function can be identified basedon their ability to bind 98P4B6 and activate a reporter construct.Typical methods are discussed for example in U.S. Pat. No. 5,928,868issued 27 Jul. 1999, and include methods for forming hybrid ligands inwhich at least one ligand is a small molecule. In an illustrativeembodiment, cells engineered to express a fusion protein of 98P4B6 and aDNA-binding protein are used to co-express a fusion protein of a hybridligand/small molecule and a cDNA library transcriptional activatorprotein. The cells further contain a reporter gene, the expression ofwhich is conditioned on the proximity of the first and second fusionproteins to each other, an event that occurs only if the hybrid ligandbinds to target sites on both hybrid proteins. Those cells that expressthe reporter gene are selected and the unknown small molecule or theunknown ligand is identified. This method provides a means ofidentifying modulators, which activate or inhibit 98P4B6.

An embodiment of this invention comprises a method of screening for amolecule that interacts with a 98P4B6 amino acid sequence shown in FIG.2 or FIG. 3, comprising the steps of contacting a population ofmolecules with a 98P4B6 amino acid sequence, allowing the population ofmolecules and the 98P4B6 amino acid sequence to interact underconditions that facilitate an interaction, determining the presence of amolecule that interacts with the 98P4B6 amino acid sequence, and thenseparating molecules that do not interact with the 98P4B6 amino acidsequence from molecules that do. In a specific embodiment, the methodfurther comprises purifying, characterizing and identifying a moleculethat interacts with the 98P4B6 amino acid sequence. The identifiedmolecule can be used to modulate a function performed by 98P4B6. In apreferred embodiment, the 98P4B6 amino acid sequence is contacted with alibrary of peptides.

X.) Therapeutic Methods and Compositions

The identification of 98P4B6 as a protein that is normally expressed ina restricted set of tissues, but which is also expressed in prostate andother cancers, opens a number of therapeutic approaches to the treatmentof such cancers. As contemplated herein, 98P4B6 functions as atranscription factor involved in activating tumor-promoting genes orrepressing genes that block tumorigenesis.

Accordingly, therapeutic approaches that inhibit the activity of a98P4B6 protein are useful for patients suffering from a cancer thatexpresses 98P4B6. These therapeutic approaches generally fall into twoclasses. One class comprises various methods for inhibiting the bindingor association of a 98P4B6 protein with its binding partner or withother proteins. Another class comprises a variety of methods forinhibiting the transcription of a 98P4B6 gene or translation of 98P4B6mRNA.

X.A.) Anti-Cancer Vaccines

The invention provides cancer vaccines comprising a 98P4B6-relatedprotein or 98P4B6-related nucleic acid. In view of the expression of98P4B6, cancer vaccines prevent and/or treat 98P4B6-expressing cancerswith minimal or no effects on non-target tissues. The use of a tumorantigen in a vaccine that generates humoral and/or cell-mediated immuneresponses as anti-cancer therapy is well known in the art and has beenemployed in prostate cancer using human PSMA and rodent PAP immunogens(Hodge et al., 1995, Int. J. Cancer 63:231-237; Fong et al., 1997, J.Immunol. 159:3113-3117).

Such methods can be readily practiced by employing a 98P4B6-relatedprotein, or a 98P4B6-encoding nucleic acid molecule and recombinantvectors capable of expressing and presenting the 98P4B6 immunogen (whichtypically comprises a number of antibody or T cell epitopes). Skilledartisans understand that a wide variety of vaccine systems for deliveryof immunoreactive epitopes are known in the art (see, e.g., Heryln etal., Ann Med 1999 Feb 31(1):66-78; Maruyama et al., Cancer ImmunolImmunother 2000 June 49(3):123-32) Briefly, such methods of generatingan immune response (e.g. humoral and/or cell-mediated) in a mammal,comprise the steps of: exposing the mammal's immune system to animmunoreactive epitope (e.g. an epitope present in a 98P4B6 proteinshown in FIG. 3 or analog or homolog thereof) so that the mammalgenerates an immune response that is specific for that epitope (e.g.generates antibodies that specifically recognize that epitope). In apreferred method, a 98P4B6 immunogen contains a biological motif, seee.g., Tables VIII-XXI and XXII-XLIX, or a peptide of a size range from98P4B6 indicated in FIG. 5, FIG. 6, FIG. 7, FIG. 8, and FIG. 9.

The entire 98P4B6 protein, immunogenic regions or epitopes thereof canbe combined and delivered by various means. Such vaccine compositionscan include, for example, lipopeptides (e.g., Vitiello, A. et al., J.Clin. Invest. 95:341, 1995), peptide compositions encapsulated inpoly(DL-lactide-co-glycolide) (“PLG”) microspheres (see, e.g., Eldridge,et al., Molec. Immunol. 28:287-294, 1991: Alonso et al., Vaccine12:299-306, 1994; Jones et al., Vaccine 13:675-681, 1995), peptidecompositions contained in immune stimulating complexes (ISCOMS) (see,e.g., Takahashi et al., Nature 344:873-875, 1990; Hu et al., Clin ExpImmunol. 113:235-243, 1998), multiple antigen peptide systems (MAPs)(see e.g., Tam, J. P., Proc. Natl. Acad. Sci. U.S.A. 85:5409-5413,1988;Tam, J. P., J. Immunol. Methods 196:17-32,1996), peptides formulated asmultivalent peptides; peptides for use in ballistic delivery systems,typically crystallized peptides, viral delivery vectors (Perkus, M. E.et al., In: Concepts in vaccine development, Kaufmann, S. H. E., ed., p.379, 1996; Chakrabarti, S. et al., Nature 320:535,1986; Hu, S. L. etal., Nature 320:537, 1986; Kieny, M.-P. et al., AIDS Bio/Technology4:790, 1986; Top, F. H. et al., J. Infect. Dis. 124:148,1971; Chanda, P.K. et al., Virology 175:535, 1990), particles of viral or syntheticorigin (e.g., Kofler, N. et al., J. Immunol. Methods. 192:25, 1996;Eldridge, J. H. et al., Sem. Hematol. 30:16, 1993; Falo, L. D., Jr. etal., Nature Med. 7:649, 1995), adjuvants (Warren, H. S., Vogel, F. R.,and Chedid, L. A. Annu. Rev. Immunol. 4:369, 1986; Gupta, R. K. et al.,Vaccine 11:293, 1993), liposomes (Reddy, R. et al., J. Immunol.148:1585,1992; Rock, K. L., Immunol. Today 17:131, 1996), or, naked orparticle absorbed cDNA (Ulmer, J. B. et al., Science 259:1745, 1993;Robinson, H. L., Hunt, L. A., and Webster, R. G., Vaccine 11:957, 1993;Shiver, J. W. et al., In: Concepts in vaccine development, Kaufmann, S.H. E., ed., p. 423, 1996; Cease, K. B., and Berzofsky, J. A., Annu. Rev.Immunol. 12:923, 1994 and Eldridge, J. H. et al., Sem. Hematol. 30:16,1993). Toxin-targeted delivery technologies, also known as receptormediated targeting, such as those of Avant Immunotherapeutics, Inc.(Needham, Mass.) may also be used.

In patients with 98P4B6-associated cancer, the vaccine compositions ofthe invention can also be used in conjunction with other treatments usedfor cancer, e.g., surgery, chemotherapy, drug therapies, radiationtherapies, etc. including use in combination with immune adjuvants suchas IL-2, IL-12, GM-CSF, and the like.

Cellular Vaccines:

CTL epitopes can be determined using specific algorithms to identifypeptides within 98P4B6 protein that bind corresponding HLA alleles (seee.g., Table IV; Epimer™ and Epimatrix™, Brown University; and, BIMAS. Ina preferred embodiment, a 98P4B6 immunogen contains one or more aminoacid sequences identified using techniques well known in the art, suchas the sequences shown in Tables VIII-XXI and XXII-XLIX or a peptide of8, 9, 10 or 11 amino acids specified by an HLA Class I motif/supermotif(e.g., Table IV (A), Table IV (D), or Table IV (E)) and/or a peptide ofat least 9 amino acids that comprises an HLA Class II motif/supermotif(e.g., Table IV (B) or Table IV (C)). As is appreciated in the art, theHLA Class I binding groove is essentially closed ended so that peptidesof only a particular size range can fit into the groove and be bound,generally HLA Class I epitopes are 8, 9, 10, or 11 amino acids long. Incontrast, the HLA Class II binding groove is essentially open ended;therefore a peptide of about 9 or more amino acids can be bound by anHLA Class II molecule. Due to the binding groove differences between HLAClass I and II, HLA Class I motifs are length specific, i.e., positiontwo of a Class I motif is the second amino acid in an amino to carboxyldirection of the peptide. The amino acid positions in a Class II motifare relative only to each other, not the overall peptide, i.e.,additional amino acids can be attached to the amino and/or carboxyltermini of a motif-bearing sequence. HLA Class II epitopes are often 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 aminoacids long, or longer than 25 amino acids.

Antibody-based Vaccines

A wide variety of methods for generating an immune response in a mammalare known in the art (for example as the first step in the generation ofhybridomas). Methods of generating an immune response in a mammalcomprise exposing the mammal's immune system to an immunogenic epitopeon a protein (e.g. a 98P4B6 protein) so that an immune response isgenerated. A typical embodiment consists of a method for generating animmune response to 98P4B6 in a host, by contacting the host with asufficient amount of at least one 98P4B6 B cell or cytotoxic T-cellepitope or analog thereof; and at least one periodic interval thereafterre-contacting the host with the 98P4B6 B cell or cytotoxic T-cellepitope or analog thereof. A specific embodiment consists of a method ofgenerating an immune response against a 98P4B6-related protein or aman-made multiepitopic peptide comprising: administering 98P4B6immunogen (e.g. a 98P4B6 protein or a peptide fragment thereof, a 98P4B6fusion protein or analog etc.) in a vaccine preparation to a human oranother mammal. Typically, such vaccine preparations further contain asuitable adjuvant (see, e.g., U.S. Pat. No. 6,146,635) or a universalhelper epitope such as a PADRE™ peptide (Epimmune Inc., San Diego,Calif.; see, e.g., Alexander et al., J. Immunol. 2000 164(3); 164(3):1625-1633; Alexander et al., Immunity 1994 1(9): 751-761 and Alexanderet al., Immunol. Res. 1998 18(2): 79-92). An alternative methodcomprises generating an immune response in an individual against a98P4B6 immunogen by: administering in vivo to muscle or skin of theindividual's body a DNA molecule that comprises a DNA sequence thatencodes a 98P4B6 immunogen, the DNA sequence operatively linked toregulatory sequences which control the expression of the DNA sequence;wherein the DNA molecule is taken up by cells, the DNA sequence isexpressed in the cells and an immune response is generated against theimmunogen (see, e.g., U.S. Pat. No. 5,962,428). Optionally a geneticvaccine facilitator such as anionic lipids; saponins; lectins;estrogenic compounds; hydroxylated lower alkyls; dimethyl sulfoxide; andurea is also administered. In addition, an antiidiotypic antibody can beadministered that mimics 98P4B6, in order to generate a response to thetarget antigen.

Nucleic Acid Vaccines:

Vaccine compositions of the invention include nucleic acid-mediatedmodalities. DNA or RNA that encode protein(s) of the invention can beadministered to a patient. Genetic immunization methods can be employedto generate prophylactic or therapeutic humoral and cellular immuneresponses directed against cancer cells expressing 98P4B6. Constructscomprising DNA encoding a 98P4B6-related protein/immunogen andappropriate regulatory sequences can be injected directly into muscle orskin of an individual, such that the cells of the muscle or skin take-upthe construct and express the encoded 98P4B6 protein/immunogen.Alternatively, a vaccine comprises a 98P4B6-related protein. Expressionof the 98P4B6-related protein immunogen results in the generation ofprophylactic or therapeutic humoral and cellular immunity against cellsthat bear a 98P4B6 protein. Various prophylactic and therapeutic geneticimmunization techniques known in the art can be used (for review, seeinformation and references published at Internet address genweb.com).Nucleic acid-based delivery is described, for instance, in Wolff et.al., Science 247:1465 (1990) as well as U.S. Pat. Nos. 5,580,859;5,589,466; 5,804,566; 5,739,118; 5,736,524; 5,679,647; WO 98/04720.Examples of DNA-based delivery technologies include “naked DNA”,facilitated (bupivicaine, polymers, peptide-mediated) delivery, cationiclipid complexes, and particle-mediated (“gene gun”) or pressure-mediateddelivery (see, e.g., U.S. Pat. No. 5,922,687).

For therapeutic or prophylactic immunization purposes, proteins of theinvention can be expressed via viral or bacterial vectors. Various viralgene delivery systems that can be used in the practice of the inventioninclude, but are not limited to, vaccinia, fowlpox, canarypox,adenovirus, influenza, poliovirus, adeno-associated virus, lentivirus,and sindbis virus (see, e.g., Restifo, 1996, Curr. Opin. Immunol.8:658-663; Tsang et al. J. Natl. Cancer Inst. 87:982-990 (1995)).Non-viral delivery systems can also be employed by introducing naked DNAencoding a 98P4B6-related protein into the patient (e.g.,intramuscularly or intradermally) to induce an anti-tumor response.

Vaccinia virus is used, for example, as a vector to express nucleotidesequences that encode the peptides of the invention. Upon introductioninto a host, the recombinant vaccinia virus expresses the proteinimmunogenic peptide, and thereby elicits a host immune response.Vaccinia vectors and methods useful in immunization protocols aredescribed in, e.g., U.S. Pat. No. 4,722,848. Another vector is BCG(Bacille Calmette Guerin). BCG vectors are described in Stover et al.,Nature 351:456460 (1991). A wide variety of other vectors useful fortherapeutic administration or immunization of the peptides of theinvention, e.g. adeno and adeno-associated virus vectors, retroviralvectors, Salmonella typhi vectors, detoxified anthrax toxin vectors, andthe like, will be apparent to those skilled in the art from thedescription herein.

Thus, gene delivery systems are used to deliver a 98P4B6-related nucleicacid molecule. In one embodiment, the full-length human 98P4B6 cDNA isemployed. In another embodiment, 98P4B6 nucleic acid molecules encodingspecific cytotoxic T lymphocyte (CTL) and/or antibody epitopes areemployed.

Ex Vivo Vaccines

Various ex vivo strategies can also be employed to generate an immuneresponse. One approach involves the use of antigen presenting cells(APCs) such as dendritic cells (DC) to present 98P4B6 antigen to apatient's immune system. Dendritic cells express MHC class I and IImolecules, B7 co-stimulator, and IL-12, and are thus highly specializedantigen presenting cells. In prostate cancer, autologous dendritic cellspulsed with peptides of the prostate-specific membrane antigen (PSMA)are being used in a Phase I clinical trial to stimulate prostate cancerpatients' immune systems (Tjoa et al., 1996, Prostate 28:65-69; Murphyet al., 1996, Prostate 29:371-380). Thus, dendritic cells can be used topresent 98P4B6 peptides to T cells in the context of MHC class I or IImolecules. In one embodiment, autologous dendritic cells are pulsed with98P4B6 peptides capable of binding to MHC class I and/or class IImolecules. In another embodiment, dendritic cells are pulsed with thecomplete 98P4B6 protein. Yet another embodiment involves engineering theoverexpression of a 98P4B6 gene in dendritic cells using variousimplementing vectors known in the art, such as adenovirus (Arthur etal., 1997, Cancer Gene Ther. 4:17-25), retrovirus (Henderson et al.,1996, Cancer Res. 56:3763-3770), lentivirus, adeno-associated virus, DNAtransfection (Ribas et al., 1997, Cancer Res. 57:2865-2869), ortumor-derived RNA transfection (Ashley et al., 1997, J. Exp. Med.186:1177-1182). Cells that express 98P4B6 can also be engineered toexpress immune modulators, such as GM-CSF, and used as immunizingagents.

X.B.) 98P4B6 as a Target for Antibody-based Therapy

98P4B6 is an attractive target for antibody-based therapeuticstrategies. A number of antibody strategies are known in the art fortargeting both extracellular and intracellular molecules (see, e.g.,complement and ADCC mediated killing as well as the use of intrabodies).Because 98P4B6 is expressed by cancer cells of various lineages relativeto corresponding normal cells, systemic administration of98P4B6-immunoreactve compositions are prepared that exhibit excellentsensitivity without toxic, non-specific and/or non-target effects causedby binding of the immunoreactive composition to non-target organs andtissues. Antibodies specifically reactive with domains of 98P4B6 areuseful to treat 98P4B6-expressing cancers systemically, either asconjugates with a toxin or therapeutic agent, or as naked antibodiescapable of inhibiting cell proliferation or function.

98P4B6 antibodies can be introduced into a patient such that theantibody binds to 98P4B6 and modulates a function, such as aninteraction with a binding partner, and consequently mediatesdestruction of the tumor cells and/or inhibits the growth of the tumorcells. Mechanisms by which such antibodies exert a therapeutic effectcan include complement-mediated cytolysis, antibody-dependent cellularcytotoxicity, modulation of the physiological function of 98P4B6,inhibition of ligand binding or signal transduction pathways, modulationof tumor cell differentiation, alteration of tumor angiogenesis factorprofiles, and/or apoptosis.

Those skilled in the art understand that antibodies can be used tospecifically target and bind immunogenic molecules such as animmunogenic region of a 98P4B6 sequence shown in FIG. 2 or FIG. 3. Inaddition, skilled artisans understand that it is routine to conjugateantibodies to cytotoxic agents (see, e.g., Slevers et al. Blood 93:113678-3684 (Jun. 1, 1999)). When cytotoxic and/or therapeutic agents aredelivered directly to cells, such as by conjugating them to antibodiesspecific for a molecule expressed by that cell (e.g. 98P4B6), thecytotoxic agent will exert its known biological effect (i.e.cytotoxicity) on those cells.

A wide variety of compositions and methods for using antibody-cytotoxicagent conjugates to kill cells are known in the art. In the context ofcancers, typical methods entail administering to an animal having atumor a biologically effective amount of a conjugate comprising aselected cytotoxic and/or therapeutic agent linked to a targeting agent(e.g. an anti-98P4B6 antibody) that binds to a marker (e.g. 98P4B6)expressed, accessible to binding or localized on the cell surfaces. Atypical embodiment is a method of delivering a cytotoxic and/ortherapeutic agent to a cell expressing 98P4B6, comprising conjugatingthe cytotoxic agent to an antibody that immunospecifically binds to a98P4B6 epitope, and, exposing the cell to the antibody-agent conjugate.Another illustrative embodiment is a method of treating an individualsuspected of suffering from metastasized cancer, comprising a step ofadministering parenterally to said individual a pharmaceuticalcomposition comprising a therapeutically effective amount of an antibodyconjugated to a cytotoxic and/or therapeutic agent.

Cancer immunotherapy using anti-98P4B6 antibodies can be done inaccordance with various approaches that have been successfully employedin the treatment of other types of cancer, including but not limited tocolon cancer (Arlen et al., 1998, Crit. Rev. Immunol. 18:133-138),multiple myeloma (Ozaki et al., 1997, Blood 90:3179-3186, Tsunenari etal., 1997, Blood 90:2437-2444), gastric cancer (Kasprzyk et al., 1992,Cancer Res. 52:2771-2776), B-cell lymphoma (Funakoshi et al., 1996, J.Immunother. Emphasis Tumor Immunol. 19:93-101), leukemia (Zhong et al.,1996, Leuk. Res. 20:581-589), colorectal cancer (Moun et al., 1994,Cancer Res. 54:6160-6166; Velders et al., 1995, Cancer Res.55:4398-4403), and breast cancer (Shepard et al., 1991, J. Clin.Immunol. 11:117-127). Some therapeutic approaches involve conjugation ofnaked antibody to a toxin or radioisotope, such as the conjugation ofY⁹¹ or I131 to anti-CD20 antibodies (e.g., Zevalin™, IDECPharmaceuticals Corp. or Bexxar™, Coulter Pharmaceuticals), while othersinvolve co-administration of antibodies and other therapeutic agents,such as Herceptin™ (trastuzumab) with paclitaxel (Genentech, Inc.). Theantibodies can be conjugated to a therapeutic agent. To treat prostatecancer, for example, 98P4B6 antibodies can be administered inconjunction with radiation, chemotherapy or hormone ablation. Also,antibodies can be conjugated to a toxin such as calicheamicin (e.g.,Mylotarg™, Wyeth-Ayerst, Madison, N.J., a recombinant humanized IgG₄kappa antibody conjugated to antitumor antibiotic calicheamicin) or amaytansinoid (e.g., taxane-based Tumor-Activated Prodrug, TAP, platform,ImmunoGen, Cambridge, Mass., also see e.g., U.S. Pat. No. 5,416,064).

Although 98P4B6 antibody therapy is useful for all stages of cancer,antibody therapy can be particularly appropriate in advanced ormetastatic cancers. Treatment with the antibody therapy of the inventionis indicated for patients who have received one or more rounds ofchemotherapy. Alternatively, antibody therapy of the invention iscombined with a chemotherapeutic or radiation regimen for patients whohave not received chemotherapeutic treatment. Additionally, antibodytherapy can enable the use of reduced dosages of concomitantchemotherapy, particularly for patients who do not tolerate the toxicityof the chemotherapeutic agent very well. Fan et al. (Cancer Res.53:46374642, 1993), Prewett et al. (International J. of Onco. 9:217-224,1996), and Hancock et al. (Cancer Res. 51:4575-4580, 1991) describe theuse of various antibodies together with chemotherapeutic agents.

Although 98P4B6 antibody therapy is useful for all stages of cancer,antibody therapy can be particularly appropriate in advanced ormetastatic cancers. Treatment with the antibody therapy of the inventionis indicated for patients who have received one or more rounds ofchemotherapy. Alternatively, antibody therapy of the invention iscombined with a chemotherapeutic or radiation regimen for patients whohave not received chemotherapeutic treatment. Additionally, antibodytherapy can enable the use of reduced dosages of concomitantchemotherapy, particularly for patients who do not tolerate the toxicityof the chemotherapeutic agent very well.

Cancer patients can be evaluated for the presence and level of 98P4B6expression, preferably using immunohistochemical assessments of tumortissue, quantitative 98P4B6 imaging, or other techniques that reliablyindicate the presence and degree of 98P4B6 expression.Immunohistochemical analysis of tumor biopsies or surgical specimens ispreferred for this purpose. Methods for immunohistochemical analysis oftumor tissues are well known in the art.

Anti-98P4B6 monoclonal antibodies that treat prostate and other cancersinclude those that initiate a potent immune response against the tumoror those that are directly cytotoxic. In this regard, anti-98P4B6monoclonal antibodies (mAbs) can elicit tumor cell lysis by eithercomplement-mediated or antibody-dependent cell cytotoxicity (ADCC)mechanisms, both of which require an intact Fc portion of theimmunoglobulin molecule for interaction with effector cell Fc receptorsites on complement proteins. In addition, anti-98P4B6 mAbs that exert adirect biological effect on tumor growth are useful to treat cancersthat express 98P4B6. Mechanisms by which directly cytotoxic mAbs actinclude: inhibition of cell growth, modulation of cellulardifferentiation, modulation of tumor angiogenesis factor profiles, andthe induction of apoptosis. The mechanism(s) by which a particularanti-98P4B6 mAb exerts an anti-tumor effect is evaluated using anynumber of in vitro assays that evaluate cell death such as ADCC, ADMMC,complement-mediated cell lysis, and so forth, as is generally known inthe art.

In some patients, the use of murine or other non-human monoclonalantibodies, or human/mouse chimeric mAbs can induce moderate to strongimmune responses against the non-human antibody. This can result inclearance of the antibody from circulation and reduced efficacy. In themost severe cases, such an immune response can lead to the extensiveformation of immune complexes which, potentially, can cause renalfailure. Accordingly, preferred monoclonal antibodies used in thetherapeutic methods of the invention are those that are either fullyhuman or humanized and that bind specifically to the target 98P4B6antigen with high affinity but exhibit low or no antigenicity in thepatient.

Therapeutic methods of the invention contemplate the administration ofsingle anti-98P4B6 mAbs as well as combinations, or cocktails, ofdifferent mAbs. Such mAb cocktails can have certain advantages inasmuchas they contain mAbs that target different epitopes, exploit differenteffector mechanisms or combine directly cytotoxic mAbs with mAbs thatrely on immune effector functionality. Such mAbs in combination canexhibit synergistic therapeutic effects. In addition, anti-98P4B6 mAbscan be administered concomitantly with other therapeutic modalities,including but not limited to various chemotherapeutic agents,androgen-blockers, immune modulators (e.g., IL-2, GM-CSF), surgery orradiation. The anti-98P4B6 mAbs are administered in their “naked” orunconjugated form, or can have a therapeutic agent(s) conjugated tothem.

Anti-98P4B6 antibody formulations are administered via any route capableof delivering the antibodies to a tumor cell. Routes of administrationinclude, but are not limited to, intravenous, intraperitoneal,intramuscular, intratumor, intradermal, and the like. Treatmentgenerally involves repeated administration of the anti-98P4B6 antibodypreparation, via an acceptable route of administration such asintravenous injection (IV), typically at a dose in the range of about0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 15, 20, or 25 mg/kg body weight. In general, doses in the range of10-1000 mg mAb per week are effective and well tolerated.

Based on clinical experience with the Herceptin™ mAb in the treatment ofmetastatic breast cancer, an initial loading dose of approximately 4mg/kg patient body weight IV, followed by weekly doses of about 2 mg/kgIV of the anti-98P4B6 mAb preparation represents an acceptable dosingregimen. Preferably, the initial loading dose is administered as a90-minute or longer infusion. The periodic maintenance dose isadministered as a 30 minute or longer infusion, provided the initialdose was well tolerated. As appreciated by those of skill in the art,various factors can influence the ideal dose regimen in a particularcase. Such factors include, for example, the binding affinity and halflife of the Ab or mAbs used, the degree of 98P4B6 expression in thepatient, the extent of circulating shed 98P4B6 antigen, the desiredsteady-state antibody concentration level, frequency of treatment, andthe influence of chemotherapeutic or other agents used in combinationwith the treatment method of the invention, as well as the health statusof a particular patient.

Optionally, patients should be evaluated for the levels of 98P4B6 in agiven sample (e.g. the levels of circulating 98P4B6 antigen and/or98P4B6 expressing cells) in order to assist in the determination of themost effective dosing regimen, etc. Such evaluations are also used formonitoring purposes throughout therapy, and are useful to gaugetherapeutic success in combination with the evaluation of otherparameters (for example, urine cytology and/or ImmunoCyt levels inbladder cancer therapy, or by analogy, serum PSA levels in prostatecancer therapy).

Anti-idiotypic anti-98P4B6 antibodies can also be used in anti-cancertherapy as a vaccine for inducing an immune response to cells expressinga 98P4B6-related protein. In particular, the generation ofanti-idiotypic antibodies is well known in the art; this methodology canreadily be adapted to generate anti-idiotypic anti-98P4B6 antibodiesthat mimic an epitope on a 98P4B6-related protein (see, for example,Wagner et al., 1997, Hybridoma 16: 33-40; Foon et al., 1995, J. Clin.Invest. 96:334-342; Herlyn et al., 1996, Cancer Immunol. Immunother.43:65-76). Such an anti-idiotypic antibody can be used in cancer vaccinestrategies.

X.C.) 98P4B6 as a Target for Cellular Immune Responses

Vaccines and methods of preparing vaccines that contain animmunogenically effective amount of one or more HLA-binding peptides asdescribed herein are further embodiments of the invention. Furthermore,vaccines in accordance with the invention encompass compositions of oneor more of the claimed peptides. A peptide can be present in a vaccineindividually. Alternatively, the peptide can exist as a homopolymercomprising multiple copies of the same peptide, or as a heteropolymer ofvarious peptides. Polymers have the advantage of increased immunologicalreaction and, where different peptide epitopes are used to make up thepolymer, the additional ability to induce antibodies and/or CTLs thatreact with different antigenic determinants of the pathogenic organismor tumor-related peptide targeted for an immune response. Thecomposition can be a naturally occurring region of an antigen or can beprepared, e.g., recombinantly or by chemical synthesis.

Carriers that can be used with vaccines of the invention are well knownin the art, and include, e.g., thyroglobulin, albumins such as humanserum albumin, tetanus toxoid, polyamino acids such as poly L-lysine,poly L-glutamic acid, influenza, hepatitis B virus core protein, and thelike. The vaccines can contain a physiologically tolerable (i.e.,acceptable) diluent such as water, or saline, preferably phosphatebuffered saline. The vaccines also typically include an adjuvant.Adjuvants such as incomplete Freund's adjuvant, aluminum phosphate,aluminum hydroxide, or alum are examples of materials well known in theart. Additionally, as disclosed herein, CTL responses can be primed byconjugating peptides of the invention to lipids, such astripalmitoyl-S-glycerylcysteinlyseryl-serine (P₃CSS). Moreover, anadjuvant such as a syntheticcytosine-phosphorothiolated-guanine-containing (CpG) oligonucleotideshas been found to increase CTL responses 10- to 100-fold. (see, e.g.Davila and Celis, J. Immunol. 165:539-547 (2000))

Upon immunization with a peptide composition in accordance with theinvention, via injection, aerosol, oral, transdermal, transmucosal,intrapleural, intrathecal, or other suitable routes, the immune systemof the host responds to the vaccine by producing large amounts of CTLsand/or HTLs specific for the desired antigen. Consequently, the hostbecomes at least partially immune to later development of cells thatexpress or overexpress 98P4B6 antigen, or derives at least sometherapeutic benefit when the antigen was tumor-associated.

In some embodiments, it may be desirable to combine the class I peptidecomponents with components that induce or facilitate neutralizingantibody and or helper T cell responses directed to the target antigen.A preferred embodiment of such a composition comprises class I and classII epitopes in accordance with the invention. An alternative embodimentof such a composition comprises a class I and/or class II epitope inaccordance with the invention, along with a cross reactive HTL epitopesuch as PADRE™ (Epimmune, San Diego, Calif.) molecule (described e.g.,in U.S. Pat. No. 5,736,142).

A vaccine of the invention can also include antigen-presenting cells(APC), such as dendritic cells (DC), as a vehicle to present peptides ofthe invention. Vaccine compositions can be created in vitro, followingdendritic cell mobilization and harvesting, whereby loading of dendriticcells occurs in vitro. For example, dendritic cells are transfected,e.g., with a minigene in accordance with the invention, or are pulsedwith peptides. The dendritic cell can then be administered to a patientto elicit immune responses in vivo. Vaccine compositions, either DNA- orpeptide-based, can also be administered in vivo in combination withdendritic cell mobilization whereby loading of dendritic cells occurs invivo.

Preferably, the following principles are utilized when selecting anarray of epitopes for inclusion in a polyepitopic composition for use ina vaccine, or for selecting discrete epitopes to be included in avaccine and/or to be encoded by nucleic acids such as a minigene. It ispreferred that each of the following principles be balanced in order tomake the selection. The multiple epitopes to be incorporated in a givenvaccine composition may be, but need not be, contiguous in sequence inthe native antigen from which the epitopes are derived.

1.) Epitopes are selected which, upon administration, mimic immuneresponses that have been observed to be correlated with tumor clearance.For HLA Class I this includes 3-4 epitopes that come from at least onetumor associated antigen (TAA). For HLA Class II a similar rationale isemployed; again 3-4 epitopes are selected from at least one TAA (see,e.g., Rosenberg et al., Science 278:1447-1450). Epitopes from one TAAmay be used in combination with epitopes from one or more additionalTAAs to produce a vaccine that targets tumors with varying expressionpatterns of frequently-expressed TAAs.

2.) Epitopes are selected that have the requisite binding affinityestablished to be correlated with immunogenicity: for HLA Class I anIC₅₀ of 500 nM or less, often 200 nM or less; and for Class II an IC₅₀of 1000 nM or less.

3.) Sufficient supermotif bearing-peptides, or a sufficient array ofallele-specific motif-bearing peptides, are selected to give broadpopulation coverage. For example, it is preferable to have at least 80%population coverage. A Monte Carlo analysis, a statistical evaluationknown in the art, can be employed to assess the breadth, or redundancyof, population coverage.

4.) When selecting epitopes from cancer-related antigens it is oftenuseful to select analogs because the patient may have developedtolerance to the native epitope.

5.) Of particular relevance are epitopes referred to as “nestedepitopes.” Nested epitopes occur where at least two epitopes overlap ina given peptide sequence. A nested peptide sequence can comprise B cell,HLA class I and/or HLA class II epitopes. When providing nestedepitopes, a general objective is to provide the greatest number ofepitopes per sequence. Thus, an aspect is to avoid providing a peptidethat is any longer than the amino terminus of the amino terminal epitopeand the carboxyl terminus of the carboxyl terminal epitope in thepeptide. When providing a multi-epitopic sequence, such as a sequencecomprising nested epitopes, it is generally important to screen thesequence in order to insure that it does not have pathological or otherdeleterious biological properties.

6.) If a polyepitopic protein is created, or when creating a minigene,an objective is to generate the smallest peptide that encompasses theepitopes of interest. This principle is similar, if not the same as thatemployed when selecting a peptide comprising nested epitopes. However,with an artificial polyepitopic peptide, the size minimization objectiveis balanced against the need to integrate any spacer sequences betweenepitopes in the polyepitopic protein. Spacer amino acid residues can,for example, be introduced to avoid junctional epitopes (an epitoperecognized by the immune system, not present in the target antigen, andonly created by the man-made juxtaposition of epitopes), or tofacilitate cleavage between epitopes and thereby enhance epitopepresentation. Junctional epitopes are generally to be avoided becausethe recipient may generate an immune response to that non-nativeepitope. Of particular concern is a junctional epitope that is a“dominant epitope.” A dominant epitope may lead to such a zealousresponse that immune responses to other epitopes are diminished orsuppressed.

7.) Where the sequences of multiple variants of the same target proteinare present, potential peptide epitopes can also be selected on thebasis of their conservancy. For example, a criterion for conservancy maydefine that the entire sequence of an HLA class I binding peptide or theentire 9-mer core of a class II binding peptide be conserved in adesignated percentage of the sequences evaluated for a specific proteinantigen.

X.C.1. Minigene Vaccines

A number of different approaches are available which allow simultaneousdelivery of multiple epitopes. Nucleic acids encoding the peptides ofthe invention are a particularly useful embodiment of the invention.Epitopes for inclusion in a minigene are preferably selected accordingto the guidelines set forth in the previous section. A preferred meansof administering nucleic acids encoding the peptides of the inventionuses minigene constructs encoding a peptide comprising one or multipleepitopes of the invention.

The use of multi-epitope minigenes is described below and in, Ishioka etal., J. Immunol. 162:3915-3925, 1999; An, L. and Whitton, J. L., J.Virol. 71:2292, 1997; Thomson, S. A. et al., J. Immunol. 157:822, 1996;Whitton, J. L. et al., J. Virol. 67:348, 1993; Hanke, R. et al., Vaccine16:426, 1998. For example, a multi-epitope DNA plasmid encodingsupermotif- and/or motif-bearing epitopes derived 98P4B6, the PADRE®universal helper T cell epitope or multiple HTL epitopes from 98P4B6(see e.g., Tables VIII-XXI and XXII to XLIX), and an endoplasmicreticulum-translocating signal sequence can be engineered. A vaccine mayalso comprise epitopes that are derived from other TAAs.

The immunogenicity of a multi-epitopic minigene can be confirmed intransgenic mice to evaluate the magnitude of CTL induction responsesagainst the epitopes tested. Further, the immunogenicity of DNA-encodedepitopes in vivo can be correlated with the in vitro responses ofspecific CTL lines against target cells transfected with the DNAplasmid. Thus, these experiments can show that the minigene serves toboth: 1.) generate a CTL response and 2.) that the induced CTLsrecognized cells expressing the encoded epitopes.

For example, to create a DNA sequence encoding the selected epitopes(minigene) for expression in human cells, the amino acid sequences ofthe epitopes may be reverse translated. A human codon usage table can beused to guide the codon choice for each amino acid. Theseepitope-encoding DNA sequences may be directly adjoined, so that whentranslated, a continuous polypeptide sequence is created. To optimizeexpression and/or immunogenicity, additional elements can beincorporated into the minigene design. Examples of amino acid sequencesthat can be reverse translated and included in the minigene sequenceinclude: HLA class I epitopes, HLA class II epitopes, antibody epitopes,a ubiquitination signal sequence, and/or an endoplasmic reticulumtargeting signal. In addition, HLA presentation of CTL and HTL epitopesmay be improved by including synthetic (e.g. poly-alanine) ornaturally-occurring flanking sequences adjacent to the CTL or HTLepitopes; these larger peptides comprising the epitope(s) are within thescope of the invention.

The minigene sequence may be converted to DNA by assemblingoligonucleotides that encode the plus and minus strands of the minigene.Overlapping oligonucleotides (30-100 bases long) may be synthesized,phosphorylated, purified and annealed under appropriate conditions usingwell known techniques. The ends of the oligonucleotides can be joined,for example, using T4 DNA ligase. This synthetic minigene, encoding theepitope polypeptide, can then be cloned into a desired expressionvector.

Standard regulatory sequences well known to those of skill in the artare preferably included in the vector to ensure expression in the targetcells. Several vector elements are desirable: a promoter with adown-stream cloning site for minigene insertion; a polyadenylationsignal for efficient transcription termination; an E. coli origin ofreplication; and an E. coli selectable marker (e.g. ampicillin orkanamycin resistance). Numerous promoters can be used for this purpose,e.g., the human cytomegalovirus (hCMV) promoter. See, e.g., U.S. Pat.Nos. 5,580,859 and 5,589,466 for other suitable promoter sequences.

Additional vector modifications may be desired to optimize minigeneexpression and immunogenicity. In some cases, introns are required forefficient gene expression, and one or more synthetic ornaturally-occurring introns could be incorporated into the transcribedregion of the minigene. The inclusion of mRNA stabilization sequencesand sequences for replication in mammalian cells may also be consideredfor increasing minigene expression.

Once an expression vector is selected, the minigene is cloned into thepolylinker region downstream of the promoter. This plasmid istransformed into an appropriate E. coli strain, and DNA is preparedusing standard techniques. The orientation and DNA sequence of theminigene, as well as all other elements included in the vector, areconfirmed using restriction mapping and DNA sequence analysis. Bacterialcells harboring the correct plasmid can be stored as a master cell bankand a working cell bank.

In addition, immunostimulatory sequences (ISSs or CpGs) appear to play arole in the immunogenicity of DNA vaccines. These sequences may beincluded in the vector, outside the minigene coding sequence, if desiredto enhance immunogenicity.

In some embodiments, a bi-cistronic expression vector which allowsproduction of both the minigene-encoded epitopes and a second protein(included to enhance or decrease immunogenicity) can be used. Examplesof proteins or polypeptides that could beneficially enhance the immuneresponse if co-expressed include cytokines (e.g., IL-2, IL-12, GM-CSF),cytokine-inducing molecules (e.g., LeIF), costimulatory molecules, orfor HTL responses, pan-DR binding proteins (PADRE™, Epimmune, San Diego,Calif.). Helper (HTL) epitopes can be joined to intracellular targetingsignals and expressed separately from expressed CTL epitopes; thisallows direction of the HTL epitopes to a cell compartment differentthan that of the CTL epitopes. If required, this could facilitate moreefficient entry of HTL epitopes into the HLA class II pathway, therebyimproving HTL induction. In contrast to HTL or CTL induction,specifically decreasing the immune response by co-expression ofimmunosuppressive molecules (e.g. TGF-β) may be beneficial in certaindiseases.

Therapeutic quantities of plasmid DNA can be produced for example, byfermentation in E. coli, followed by purification. Aliquots from theworking cell bank are used to inoculate growth medium, and grown tosaturation in shaker flasks or a bioreactor according to well-knowntechniques. Plasmid DNA can be purified using standard bioseparationtechnologies such as solid phase anion-exchange resins supplied byQIAGEN, Inc. (Valencia, Calif.). If required, supercoiled DNA can beisolated from the open circular and linear forms using gelelectrophoresis or other methods.

Purified plasmid DNA can be prepared for injection using a variety offormulations. The simplest of these is reconstitution of lyophilized DNAin sterile phosphate-buffer saline (PBS). This approach, known as “nakedDNA,” is currently being used for intramuscular (IM) administration inclinical trials. To maximize the immunotherapeutic effects of minigeneDNA vaccines, an alternative method for formulating purified plasmid DNAmay be desirable. A variety of methods have been described, and newtechniques may become available. Cationic lipids, glycolipids, andfusogenic liposomes can also be used in the formulation (see, e.g., asdescribed by WO 93/24640; Mannino & Gould-Fogerite, BioTechniques 6(7):682 (1988); U.S. Pat No. 5,279,833; WO 91/06309; and Felgner, et al.,Proc. Nat'l Acad. Sci. USA 84:7413 (1987). In addition, peptides andcompounds referred to collectively as protective, interactive,non-condensing compounds (PINC) could also be complexed to purifiedplasmid DNA to influence variables such as stability, intramusculardispersion, or trafficking to specific organs or cell types.

Target cell sensitization can be used as a functional assay forexpression and HLA class I presentation of minigene-encoded CTLepitopes. For example, the plasmid DNA is introduced into a mammaliancell line that is suitable as a target for standard CTL chromium releaseassays. The transfection method used will be dependent on the finalformulation. Electroporation can be used for “naked” DNA, whereascationic lipids allow direct in vitro transfection. A plasmid expressinggreen fluorescent protein (GFP) can be co-transfected to allowenrichment of transfected cells using fluorescence activated cellsorting (FACS). These cells are then chromium-51 (⁵¹Cr) labeled and usedas target cells for epitope-specific CTL lines; cytolysis, detected by⁵¹Cr release, indicates both production of, and HLA presentation of,minigene-encoded CTL epitopes. Expression of HTL epitopes may beevaluated in an analogous manner using assays to assess HTL activity.

In vivo immunogenicity is a second approach for functional testing ofminigene DNA formulations. Transgenic mice expressing appropriate humanHLA proteins are immunized with the DNA product. The dose and route ofadministration are formulation dependent (e.g., IM for DNA in PBS,intraperitoneal (i.p.) for lipid-complexed DNA). Twenty-one days afterimmunization, splenocytes are harvested and restimulated for one week inthe presence of peptides encoding each epitope being tested. Thereafter,for CTL effector cells, assays are conducted for cytolysis ofpeptide-loaded, ⁵¹Cr-labeled target cells using standard techniques.Lysis of target cells that were sensitized by HLA loaded with peptideepitopes, corresponding to minigene-encoded epitopes, demonstrates DNAvaccine function for in vivo induction of CTLs. Immunogenicity of HTLepitopes is confirmed in transgenic mice in an analogous manner.

Alternatively, the nucleic acids can be administered using ballisticdelivery as described, for instance, in U.S. Pat. No. 5,204,253. Usingthis technique, particles comprised solely of DNA are administered. In afurther alternative embodiment, DNA can be adhered to particles, such asgold particles.

Minigenes can also be delivered using other bacterial or viral deliverysystems well known in the art, e.g., an expression construct encodingepitopes of the invention can be incorporated into a viral vector suchas vaccinia.

X.C.2. Combinations of CTL Peptides with Helper Peptides

Vaccine compositions comprising CTL peptides of the invention can bemodified, e.g., analoged, to provide desired attributes, such asimproved serum half life, broadened population coverage or enhancedimmunogenicity.

For instance, the ability of a peptide to induce CTL activity can beenhanced by linking the peptide to a sequence which contains at leastone epitope that is capable of inducing a T helper cell response.Although a CTL peptide can be directly linked to a T helper peptide,often CTL epitope/HTL epitope conjugates are linked by a spacermolecule. The spacer is typically comprised of relatively small, neutralmolecules, such as amino acids or amino acid mimetics, which aresubstantially uncharged under physiological conditions. The spacers aretypically selected from, e.g., Ala, Gly, or other neutral spacers ofnonpolar amino acids or neutral polar amino acids. It will be understoodthat the optionally present spacer need not be comprised of the sameresidues and thus may be a hetero- or homo-oligomer. When present, thespacer will usually be at least one or two residues, more usually threeto six residues and sometimes 10 or more residues. The CTL peptideepitope can be linked to the T helper peptide epitope either directly orvia a spacer either at the amino or carboxy terminus of the CTL peptide.The amino terminus of either the immunogenic peptide or the T helperpeptide may be acylated.

In certain embodiments, the T helper peptide is one that is recognizedby T helper cells present in a majority of a genetically diversepopulation. This can be accomplished by selecting peptides that bind tomany, most, or all of the HLA class II molecules. Examples of such aminoacid bind many HLA Class II molecules include sequences from antigenssuch as tetanus toxoid at positions 830-843 (QYIKANSKFIGITE; SEQ ID NO:97), Plasmodium falciparum circumsporozoite (CS) protein at positions378-398 (DIEKKIAKMEKASSVFNWNS; SEQ ID NO: 98), and Streptococcus 18 kDprotein at positions 116-131 (GAVDSILGGVATYGAA; SEQ ID NO: 99). Otherexamples include peptides bearing a DR 1-4-7 supermotif, or either ofthe DR3 motifs.

Alternatively, it is possible to prepare synthetic peptides capable ofstimulating T helper lymphocytes, in a loosely HLA-restricted fashion,using amino acid sequences not found in nature (see, e.g., PCTpublication WO 95/07707). These synthetic compounds calledPan-DR-binding epitopes (e.g., PADRE™, Epimmune, Inc., San Diego,Calif.) are designed, most preferably, to bind most HLA-DR (human HLAclass II) molecules. For instance, a pan-DR-binding epitope peptidehaving the formula: XKXVAAWTLKAAX (SEQ ID NO: 100), where “X” is eithercyclohexylalanine, phenylalanine, or tyrosine, and a is either D-alanineor L-alanine, has been found to bind to most HLA-DR alleles, and tostimulate the response of T helper lymphocytes from most individuals,regardless of their HLA type. An alternative of a pan-DR binding epitopecomprises all “L” natural amino acids and can be provided in the form ofnucleic acids that encode the epitope.

HTL peptide epitopes can also be modified to alter their biologicalproperties. For example, they can be modified to include D-amino acidsto increase their resistance to proteases and thus extend their serumhalf life, or they can be conjugated to other molecules such as lipids,proteins, carbohydrates, and the like to increase their biologicalactivity. For example, a T helper peptide can be conjugated to one ormore palmitic acid chains at either the amino or carboxyl termini.

X.C.3. Combinations of CTL Peptides with T Cell Priming Agents

In some embodiments it may be desirable to include in the pharmaceuticalcompositions of the invention at least one component which primes Blymphocytes or T lymphocytes. Lipids have been identified as agentscapable of priming CTL in vivo. For example, palmitic acid residues canbe attached to the ε-and α-amino groups of a lysine residue and thenlinked, e.g., via one or more linking residues such as Gly, Gly-Gly-,Ser, Ser-Ser, or the like, to an immunogenic peptide. The lipidatedpeptide can then be administered either directly in a micelle orparticle, incorporated into a liposome, or emulsified in an adjuvant,e.g., incomplete Freund's adjuvant. In a preferred embodiment, aparticularly effective immunogenic composition comprises palmitic acidattached to ε- and α-amino groups of Lys, which is attached via linkage,e.g., Ser-Ser, to the amino terminus of the immunogenic peptide.

As another example of lipid priming of CTL responses, E. colilipoproteins, such as tripalmitoyl-S-glycerylcysteinlyseryl- serine(P₃CSS) can be used to prime virus specific CTL when covalently attachedto an appropriate peptide (see, e.g., Deres, et al., Nature 342:561,1989). Peptides of the invention can be coupled to P₃CSS, for example,and the lipopeptide administered to an individual to prime specificallyan immune response to the target antigen. Moreover, because theinduction of neutralizing antibodies can also be primed withP₃CSS-conjugated epitopes, two such compositions can be combined to moreeffectively elicit both humoral and cell-mediated responses.

X.C.4. Vaccine Compositions Comprising DC Pulsed with CTL and/or HTLPeptides

An embodiment of a vaccine composition in accordance with the inventioncomprises ex vivo administration of a cocktail of epitope-bearingpeptides to PBMC, or isolated DC therefrom, from the patient's blood. Apharmaceutical to facilitate harvesting of DC can be used, such asProgenipoietin™ (Pharmacia-Monsanto, St. Louis, Mo.) or GM-CSF/IL-4.After pulsing the DC with peptides and prior to reinfusion intopatients, the DC are washed to remove unbound peptides. In thisembodiment, a vaccine comprises peptide-pulsed DCs which present thepulsed peptide epitopes complexed with HLA molecules on their surfaces.

The DC can be pulsed ex vivo with a cocktail of peptides, some of whichstimulate CTL responses to 98P4B6. Optionally, a helper T cell (HTL)peptide, such as a natural or artificial loosely restricted HLA Class IIpeptide, can be included to facilitate the CTL response. Thus, a vaccinein accordance with the invention is used to treat a cancer whichexpresses or overexpresses 98P4B6.

X.D. Adoptive Immunotherapy

Antigenic 98P4B6-related peptides are used to elicit a CTL and/or HTLresponse ex vivo, as well. The resulting CTL or HTL cells, can be usedto treat tumors in patients that do not respond to other conventionalforms of therapy, or will not respond to a therapeutic vaccine peptideor nucleic acid in accordance with the invention. Ex vivo CTL or HTLresponses to a particular antigen are induced by incubating in tissueculture the patient's, or genetically compatible, CTL or HTL precursorcells together with a source of antigen-presenting cells (APC), such asdendritic cells, and the appropriate immunogenic peptide. After anappropriate incubation time (typically about 7-28 days), in which theprecursor cells are activated and expanded into effector cells, thecells are infused back into the patient, where they will destroy (CTL)or facilitate destruction (HTL) of their specific target cell (e.g., atumor cell). Transfected dendritic cells may also be used as antigenpresenting cells.

X.E. Administration of Vaccines for Therapeutic or Prophylactic Purposes

Pharmaceutical and vaccine compositions of the invention are typicallyused to treat and/or prevent a cancer that expresses or overexpresses98P4B6. In therapeutic applications, peptide and/or nucleic acidcompositions are administered to a patient in an amount sufficient toelicit an effective B cell, CTL and/or HTL response to the antigen andto cure or at least partially arrest or slow symptoms and/orcomplications. An amount adequate to accomplish this is defined as“therapeutically effective dose.” Amounts effective for this use willdepend on, e.g., the particular composition administered, the manner ofadministration, the stage and severity of the disease being treated, theweight and general state of health of the patient, and the judgment ofthe prescribing physician.

For pharmaceutical compositions, the immunogenic peptides of theinvention, or DNA encoding them, are generally administered to anindividual already bearing a tumor that expresses 98P4B6. The peptidesor DNA encoding them can be administered individually or as fusions ofone or more peptide sequences. Patients can be treated with theimmunogenic peptides separately or in conjunction with other treatments,such as surgery, as appropriate.

For therapeutic use, administration should generally begin at the firstdiagnosis of 98P4B6-associated cancer. This is followed by boostingdoses until at least symptoms are substantially abated and for a periodthereafter. The embodiment of the vaccine composition (i.e., including,but not limited to embodiments such as peptide cocktails, polyepitopicpolypeptides, minigenes, or TAA-specific CTLs or pulsed dendritic cells)delivered to the patient may vary according to the stage of the diseaseor the patient's health status. For example, in a patient with a tumorthat expresses 98P4B6, a vaccine comprising 98P4B6-specific CTL may bemore efficacious in killing tumor cells in patient with advanced diseasethan alternative embodiments.

It is generally important to provide an amount of the peptide epitopedelivered by a mode of administration sufficient to stimulateeffectively a cytotoxic T cell response; compositions which stimulatehelper T cell responses can also be given in accordance with thisembodiment of the invention.

The dosage for an initial therapeutic immunization generally occurs in aunit dosage range where the lower value is about 1, 5, 50, 500, or 1,000μg and the higher value is about 10,000; 20,000; 30,000; or 50,000 μg.Dosage values for a human typically range from about 500 μg to about50,000 μg per 70 kilogram patient. Boosting dosages of between about 1.0μg to about 50,000 μg of peptide pursuant to a boosting regimen overweeks to months may be administered depending upon the patient'sresponse and condition as determined by measuring the specific activityof CTL and HTL obtained from the patent's blood. Administration shouldcontinue until at least clinical symptoms or laboratory tests indicatethat the neoplasia, has been eliminated or reduced and for a periodthereafter. The dosages, routes of administration, and dose schedulesare adjusted in accordance with methodologies known in the art.

In certain embodiments, the peptides and compositions of the presentinvention are employed in serious disease states, that is,life-threatening or potentially life threatening situations. In suchcases, as a result of the minimal amounts of extraneous substances andthe relative nontoxic nature of the peptides in preferred compositionsof the invention, it is possible and may be felt desirable by thetreating physician to administer substantial excesses of these peptidecompositions relative to these stated dosage amounts.

The vaccine compositions of the invention can also be used purely asprophylactic agents. Generally the dosage for an initial prophylacticimmunization generally occurs in a unit dosage range where the lowervalue is about 1, 5, 50, 500, or 1000 μg and the higher value is about10,000; 20,000; 30,000; or 50,000 μg. Dosage values for a humantypically range from about 500 μg to about 50,000 μg per 70 kilogrampatient. This is followed by boosting dosages of between about 1.0 μg toabout 50,000 μg of peptide administered at defined intervals from aboutfour weeks to six months after the initial administration of vaccine.The immunogenicity of the vaccine can be assessed by measuring thespecific activity of CTL and HTL obtained from a sample of the patient'sblood.

The pharmaceutical compositions for therapeutic treatment are intendedfor parenteral, topical, oral, nasal, intrathecal, or local (e.g. as acream or topical ointment) administration. Preferably, thepharmaceutical compositions are administered parentally, e.g.,intravenously, subcutaneously, intradermally, or intramuscularly. Thus,the invention provides compositions for parenteral administration whichcomprise a solution of the immunogenic peptides dissolved or suspendedin an acceptable carrier, preferably an aqueous carrier.

A variety of aqueous carriers may be used, e.g., water, buffered water,0.8% saline, 0.3% glycine, hyaluronic acid and the like. Thesecompositions may be sterilized by conventional, well-known sterilizationtechniques, or may be sterile filtered. The resulting aqueous solutionsmay be packaged for use as is, or lyophilized, the lyophilizedpreparation being combined with a sterile solution prior toadministration.

The compositions may contain pharmaceutically acceptable auxiliarysubstances as required to approximate physiological conditions, such aspH-adjusting and buffering agents, tonicity adjusting agents, wettingagents, preservatives, and the like, for example, sodium acetate, sodiumlactate, sodium chloride, potassium chloride, calcium chloride, sorbitanmonolaurate, triethanolamine oleate, etc.

The concentration of peptides of the invention in the pharmaceuticalformulations can vary widely, i.e., from less than about 0.1%, usuallyat or at least about 2% to as much as 20% to 50% or more by weight, andwill be selected primarily by fluid volumes, viscosities, etc., inaccordance with the particular mode of administration selected.

A human unit dose form of a composition is typically included in apharmaceutical composition that comprises a human unit dose of anacceptable carrier, in one embodiment an aqueous carrier, and isadministered in a volume/quantity that is known by those of skill in theart to be used for administration of such compositions to humans (see,e.g., Remington's Pharmaceutical Sciences, 17^(th) Edition, A. Gennaro,Editor, Mack Publishing Co., Easton, Pa., 1985). For example a peptidedose for initial immunization can be from about 1 to about 50,000 μg,generally 100-5,000 μg, for a 70 kg patient. For example, for nucleicacids an initial immunization may be performed using an expressionvector in the form of naked nucleic acid administered IM (or SC or ID)in the amounts of 0.5-5 mg at multiple sites. The nucleic acid (0.1 to1000 μg) can also be administered using a gene gun. Following anincubation period of 34 weeks, a booster dose is then administered. Thebooster can be recombinant fowlpox virus administered at a dose of 5-10⁷to 5×10⁹ pfu.

For antibodies, a treatment generally involves repeated administrationof the anti-98P4B6 antibody preparation, via an acceptable route ofadministration such as intravenous injection (IV), typically at a dosein the range of about 0.1 to about 10 mg/kg body weight. In general,doses in the range of 10-500 mg mAb per week are effective and welltolerated. Moreover, an initial loading dose of approximately 4 mg/kgpatient body weight IV, followed by weekly doses of about 2 mg/kg IV ofthe anti-98P4B6 mAb preparation represents an acceptable dosing regimen.As appreciated by those of skill in the art, various factors caninfluence the ideal dose in a particular case. Such factors include, forexample, half life of a composition, the binding affinity of an Ab, theimmunogenicity of a substance, the degree of 98P4B6 expression in thepatient, the extent of circulating shed 98P4B6 antigen, the desiredsteady-state concentration level, frequency of treatment, and theinfluence of chemotherapeutic or other agents used in combination withthe treatment method of the invention, as well as the health status of aparticular patent. Non-limiting preferred human unit doses are, forexample, 500 μg -1 mg, 1 mg-50 mg, 50 mg-100 mg, 100 mg-200 mg, 200mg-300 mg, 400 mg-500 mg, 500 mg-600 mg, 600 mg-700 mg, 700 mg-800mg,800 mg-900 mg, 900 mg-1 g, or 1 mg-700 mg. In certain embodiments, thedose is in a range of 2-5 mg/kg body weight, e.g., with follow on weeklydoses of 1-3 mg/kg; 0.5 mg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 mg/kg bodyweight followed, e.g., in two, three or four weeks by weekly doses;0.5-10 mg/kg body weight, e.g., followed in two, three or four weeks byweekly doses; 225, 250, 275, 300, 325, 350, 375, 400 mg m² of body areaweekly; 1-600 mg m² of body area weekly; 225-400 mg m² of body areaweekly; these does can be followed by weekly doses for 2, 3, 4, 5, 6, 7,8, 9, 19, 11, 12 or more weeks.

In one embodiment, human unit dose forms of polynucleotides comprise asuitable dosage range or effective amount that provides any therapeuticeffect. As appreciated by one of ordinary skill in the art a therapeuticeffect depends on a number of factors, including the sequence of thepolynucleotide, molecular weight of the polynucleotide and route ofadministration. Dosages are generally selected by the physician or otherhealth care professional in accordance with a variety of parametersknown in the art, such as severity of symptoms, history of the patientand the like. Generally, for a polynucleotide of about 20 bases, adosage range may be selected from, for example, an independentlyselected lower limit such as about 0.1, 0.25, 0.5, 1, 2, 5, 10, 20, 30,40, 50, 60, 70, 80, 90, 100, 200, 300, 400 or 500 mg/kg up to anindependently selected upper limit, greater than the lower limit, ofabout 60, 80, 100, 200, 300, 400, 500, 750, 1000, 1500, 2000, 3000,4000, 5000, 6000, 7000, 8000, 9000 or 10,000 mg/kg. For example, a dosemay be about any of the following: 0.1 to 100 mg/kg, 0.1 to 50 mg/kg,0.1 to 25 mg/kg, 0.1 to 10 mg/kg, 1 to 500 mg/kg, 100 to 400 mg/kg, 200to 300 mg/kg, 1 to 100 mg/kg, 100 to 200 mg/kg, 300 to 400 mg/kg, 400 to500 mg/kg, 500 to 1000 mg/kg, 500 to 5000 mg/kg, or 500 to 10,000 mg/kg.Generally, parenteral routes of administration may require higher dosesof polynucleotide compared to more direct application to the nucleotideto diseased tissue, as do polynucleotides of increasing length.

In one embodiment, human unit dose forms of T-cells comprise a suitabledosage range or effective amount that provides any therapeutic effect.As appreciated by one of ordinary skill in the art, a therapeutic effectdepends on a number of factors. Dosages are generally selected by thephysician or other health care professional in accordance with a varietyof parameters known in the art, such as severity of symptoms, history ofthe patient and the like. A dose may be about 10⁴ cells to about 10⁶cells, about 10⁶ cells to about 10⁸ cells, about 10⁸ to about 10¹¹cells, or about 10⁸ to about 5×10¹⁰ cells. A dose may also about 10⁶cells/m² to about 10¹⁰ cells/m², or about 10⁶ cells/m² to about 10⁸cells/m².

Proteins(s) of the invention, and/or nucleic acids encoding theprotein(s), can also be administered via liposomes, which may also serveto: 1) target the proteins(s) to a particular tissue, such as lymphoidissue; 2) to target selectively to diseases cells; or, 3) to increasethe half-life of the peptide composition. Liposomes include emulsions,foams, micelles, insoluble monolayers, liquid crystals, phospholipiddispersions, lamellar layers and the like. In these preparations, thepeptide to be delivered is incorporated as part of a liposome, alone orin conjunction with a molecule which binds to a receptor prevalent amonglymphoid cells, such as monoclonal antibodies which bind to the CD45antigen, or with other therapeutic or immunogenic compositions. Thus,liposomes either filled or decorated with a desired peptide of theinvention can be directed to the site of lymphoid cells, where theliposomes then deliver the peptide compositions. Liposomes for use inaccordance with the invention are formed from standard vesicle-forminglipids, which generally include neutral and negatively chargedphospholipids and a sterol, such as cholesterol. The selection of lipidsis generally guided by consideration of, e.g., liposome size, acidlability and stability of the liposomes in the blood stream. A varietyof methods are available for preparing liposomes, as described in, e.g.,Szoka, et al., Ann. Rev. Biophys. Bioeng. 9:467 (1980), and U.S. Pat.Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

For targeting cells of the immune system, a ligand to be incorporatedinto the liposome can include, e.g., antibodies or fragments thereofspecific for cell surface determinants of the desired immune systemcells. A liposome suspension containing a peptide may be administeredintravenously, locally, topically, etc. in a dose which varies accordingto, inter alia, the manner of administration, the peptide beingdelivered, and the stage of the disease being treated.

For solid compositions, conventional nontoxic solid carriers may be usedwhich include, for example, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. For oraladministration, a pharmaceutically acceptable nontoxic composition isformed by incorporating any of the normally employed excipients, such asthose carriers previously listed, and generally 10-95% of activeingredient, that is, one or more peptides of the invention, and morepreferably at a concentration of 25%-75%.

For aerosol administration, immunogenic peptides are preferably suppliedin finely divided form along with a surfactant and propellant. Typicalpercentages of peptides are about 0.01%-20% by weight, preferably about1%-i 0%. The surfactant must, of course, be nontoxic, and preferablysoluble in the propellant. Representative of such agents are the estersor partial esters of fatty acids containing from about 6 to 22 carbonatoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic,linolenic, olesteric and oleic acids with an aliphatic polyhydricalcohol or its cyclic anhydride. Mixed esters, such as mixed or naturalglycerides may be employed. The surfactant may constitute about 0.1%-20%by weight of the composition, preferably about 0.25-5%. The balance ofthe composition is ordinarily propellant. A carrier can also beincluded, as desired, as with, e.g., lecithin for intranasal delivery.

XI.) Diagnostic and Prognostic Embodiments of 98P4B6.

As disclosed herein, 98P4B6 polynucleotides, polypeptides, reactivecytotoxic T cells (CTL), reactive helper T cells (HTL) andanti-polypeptide antibodies are used in well known diagnostic,prognostic and therapeutic assays that examine conditions associatedwith dysregulated cell growth such as cancer, in particular the cancerslisted in Table I (see, e.g., both its specific pattern of tissueexpression as well as its overexpression in certain cancers as describedfor example in the Example entitled “Expression analysis of 98P4B6 innormal tissues, and patient specimens”).

98P4B6 can be analogized to a prostate associated antigen PSA, thearchetypal marker that has been used by medical practitioners for yearsto identify and monitor the presence of prostate cancer (see, e.g.,Merrill et al., J. Urol. 163(2): 503-5120 (2000); Polascik et al., J.Urol. Aug; 162(2):293-306 (1999) and Fortier et al., J. Nat. CancerInst. 91(19): 1635-1640(1999)). A variety of other diagnostic markersare also used in similar contexts including p53 and K-ras (see, e.g.,Tulchinsky et al., Int J Mol Med 1999 Jul. 4(1):99-102 and Minimoto etal., Cancer Detect Prev 2000;24(1):1-12). Therefore, this disclosure of98P4B6 polynucleotides and polypeptides (as well as 98P4B6polynucleotide probes and anti-98P4B6 antibodies used to identify thepresence of these molecules) and their properties allows skilledartisans to utilize these molecules in methods that are analogous tothose used, for example, in a variety of diagnostic assays directed toexamining conditions associated with cancer.

Typical embodiments of diagnostic methods which utilize the 98P4B6polynucleotides, polypeptides, reactive T cells and antibodies areanalogous to those methods from well-established diagnostic assays,which employ, e.g., PSA polynucleotides, polypeptides, reactive T cellsand antibodies. For example, just as PSA polynucleotides are used asprobes (for example in Northern analysis, see, e.g., Sharief et al.,Biochem. Mol. Biol. Int. 33(3):567-74(1994)) and primers (for example inPCR analysis, see, e.g., Okegawa et al., J. Urol. 163(4): 1189-1190(2000)) to observe the presence and/or the level of PSA mRNAs in methodsof monitoring PSA overexpression or the metastasis of prostate cancers,the 98P4B6 polynucleotides described herein can be utilized in the sameway to detect 98P4B6 overexpression or the metastasis of prostate andother cancers expressing this gene. Alternatively, just as PSApolypeptides are used to generate antibodies specific for PSA which canthen be used to observe the presence and/or the level of PSA proteins inmethods to monitor PSA protein overexpression (see, e.g., Stephan etal., Urology 55(4):560-3 (2000)) or the metastasis of prostate cells(see, e.g., Alanen et al., Pathol. Res. Pract. 192(3):233-7 (1996)), the98P4B6 polypeptides described herein can be utilized to generateantibodies for use in detecting 98P4B6 overexpression or the metastasisof prostate cells and cells of other cancers expressing this gene.

Specifically, because metastases involves the movement of cancer cellsfrom an organ of origin (such as the lung or prostate gland etc.) to adifferent area of the body (such as a lymph node), assays which examinea biological sample for the presence of cells expressing 98P4B6polynucleotides and/or polypeptides can be used to provide evidence ofmetastasis. For example, when a biological sample from tissue that doesnot normally contain 98P4B6-expressing cells (lymph node) is found tocontain 98P4B6-expressing cells such as the 98P4B6 expression seen inLAPC4 and LAPC9, xenografts isolated from lymph node and bonemetastasis, respectively, this finding is indicative of metastasis.

Alternatively 98P4B6 polynucleotides and/or polypeptides can be used toprovide evidence of cancer, for example, when cells in a biologicalsample that do not normally express 98P4B6 or express 98P4B6 at adifferent level are found to express 98P4B6 or have an increasedexpression of 98P4B6 (see, e.g., the 98P4B6 expression in the cancerslisted in Table I and in patient samples etc. shown in the accompanyingFigures). In such assays, artisans may further wish to generatesupplementary evidence of metastasis by testing the biological samplefor the presence of a second tissue restricted marker (in addition to98P4B6) such as PSA, PSCA etc. (see, e.g., Alanen et al., Pathol. Res.Pract. 192(3): 233-237 (1996)).

Just as PSA polynucleotide fragments and polynucleotide variants areemployed by skilled artisans for use in methods of monitoring PSA,98P4B6 polynucleotide fragments and polynucleotide variants are used inan analogous manner. In particular, typical PSA polynucleotides used inmethods of monitoring PSA are probes or primers which consist offragments of the PSA cDNA sequence. Illustrating this, primers used toPCR amplify a PSA polynucleotide must include less than the whole PSAsequence to function in the polymerase chain reaction. In the context ofsuch PCR reactions, skilled artisans generally create a variety ofdifferent polynucleotide fragments that can be used as primers in orderto amplify different portions of a polynucleotide of interest or tooptimize amplification reactions (see, e.g., Caetano-Anolles, G.Biotechniques 25(3): 472476, 478-480 (1998); Robertson et al., MethodsMol. Biol. 98:121-154 (1998)). An additional illustration of the use ofsuch fragments is provided in the Example entitled “Expression analysisof 98P4B6 in normal tissues, and patient specimens,” where a 98P4B6polynucleotide fragment is used as a probe to show the expression of98P4B6 RNAs in cancer cells. In addition, variant polynucleotidesequences are typically used as primers and probes for the correspondingmRNAs in PCR and Northern analyses (see, e.g., Sawai et al., Fet alDiagn. Ther. 1996 Nov-Dec 11(6):407-13 and Current Protocols InMolecular Biology, Volume 2, Unit 2, Frederick M. Ausubel et el. eds.,1995)). Polynucleotide fragments and variants are useful in this contextwhere they are capable of binding to a target polynucleotide sequence(e.g., a 98P4B6 polynucleotide shown in FIG. 2 or variant thereof) underconditions of high stringency.

Furthermore, PSA polypeptides which contain an epitope that can berecognized by an antibody or T cell that specifically binds to thatepitope are used in methods of monitoring PSA. 98P4B6 polypeptidefragments and polypeptide analogs or variants can also be used in ananalogous manner. This practice of using polypeptide fragments orpolypeptide variants to generate antibodies (such as anti-PSA antibodiesor T cells) is typical in the art with a wide variety of systems such asfusion proteins being used by practitioners (see, e.g., CurrentProtocols In Molecular Biology, Volume 2, Unit 16, Frederick M. Ausubelet al. eds., 1995). In this context, each epitope(s) functions toprovide the architecture with which an antibody or T cell is reactive.Typically, skilled artisans create a variety of different polypeptidefragments that can be used in order to generate immune responsesspecific for different portions of a polypeptide of interest (see, e.g.,U.S. Pat. No. 5,840,501 and U.S. Pat. No. 5,939,533). For example it maybe preferable to utilize a polypeptide comprising one of the 98P4B6biological motifs discussed herein or a motif-bearing subsequence whichis readily identified by one of skill in the art based on motifsavailable in the art. Polypeptide fragments, variants or analogs aretypically useful in this context as long as they comprise an epitopecapable of generating an antibody or T cell specific for a targetpolypeptide sequence (e.g. a 98P4B6 polypeptide shown in FIG. 3).

As shown herein, the 98P4B6 polynucleotides and polypeptides (as well asthe 98P4B6 polynucleotide probes and anti-98P4B6 antibodies or T cellsused to identify the presence of these molecules) exhibit specificproperties that make them useful in diagnosing cancers such as thoselisted in Table I. Diagnostic assays that measure the presence of 98P4B6gene products, in order to evaluate the presence or onset of a diseasecondition described herein, such as prostate cancer, are used toidentify patients for preventive measures or further monitoring, as hasbeen done so successfully with PSA. Moreover, these materials satisfy aneed in the art for molecules having similar or complementarycharacteristics to PSA in situations where, for example, a definitediagnosis of metastasis of prostatic origin cannot be made on the basisof a test for PSA alone (see, e.g., Alanen et al., Pathol. Res. Pract.192(3): 233-237 (1996)), and consequently, materials such as 98P4B6polynucleotides and polypeptides (as well as the 98P4B6 polynucleotideprobes and anti-98P4B6 antibodies used to identify the presence of thesemolecules) need to be employed to confirm a metastases of prostaticorigin.

Finally, in addition to their use in diagnostic assays, the 98P4B6polynucleotides disclosed herein have a number of other utilities suchas their use in the identification of oncogenetic associated chromosomalabnormalities in the chromosomal region to which the 98P4B6 gene maps(see the Example entitled “Chromosomal Mapping of 98P4B6” below).Moreover, in addition to their use in diagnostic assays, the98P4B6-related proteins and polynucleotides disclosed herein have otherutilities such as their use in the forensic analysis of tissues ofunknown origin (see, e.g., Takahama K Forensic Sci Int 1996 Jun.28;80(1-2): 63-9).

Additionally, 98P4B6-related proteins or polynucleotides of theinvention can be used to treat a pathologic condition characterized bythe over-expression of 98P4B6. For example, the amino acid or nucleicacid sequence of FIG. 2 or FIG. 3, or fragments of either, can be usedto generate an immune response to a 98P4B6 antigen. Antibodies or othermolecules that react with 98P4B6 can be used to modulate the function ofthis molecule, and thereby provide a therapeutic benefit.

XII.) Inhibition of 98P4B6 Protein Function

The invention includes various methods and compositions for inhibitingthe binding of 98P4B6 to its binding partner or its association withother protein(s) as well as methods for inhibiting 98P4B6 function.

XII.A.) Inhibition of 98P4B6 With Intracellular Antibodies

In one approach, a recombinant vector that encodes single chainantibodies that specifically bind to 98P4B6 are introduced into 98P4B6expressing cells via gene transfer technologies. Accordingly, theencoded single chain anti-98P4B6 antibody is expressed intracellularly,binds to 98P4B6 protein, and thereby inhibits its function. Methods forengineering such intracellular single chain antibodies are well known.Such intracellular antibodies, also known as “intrabodies”, arespecifically targeted to a particular compartment within the cell,providing control over where the inhibitory activity of the treatment isfocused. This technology has been successfully applied in the art (forreview, see Richardson and Marasco, 1995, TIBTECH vol. 13). Intrabodieshave been shown to virtually eliminate the expression of otherwiseabundant cell surface receptors (see, e.g., Richardson et al., 1995,Proc. Natl. Acad. Sci. USA 92: 3137-3141; Beerli et al., 1994, J. Biol.Chem. 289: 23931-23936; Deshane et a., 1994, Gene Ther. 1: 332-337).

Single chain antibodies comprise the variable domains of the heavy andlight chain joined by a flexible linker polypeptide, and are expressedas a single polypeptide. Optionally, single chain antibodies areexpressed as a single chain variable region fragment joined to the lightchain constant region. Well-known intracellular trafficking signals areengineered into recombinant polynucleotide vectors encoding such singlechain antibodies in order to target precisely the intrabody to thedesired intracellular compartment. For example, intrabodies targeted tothe endoplasmic reticulum (ER) are engineered to incorporate a leaderpeptide and, optionally, a C-terminal ER retention signal, such as theKDEL amino acid motif. Intrabodies intended to exert activity in thenucleus are engineered to include a nuclear localization signal. Lipidmoieties are joined to intrabodies in order to tether the intrabody tothe cytosolic side of the plasma membrane. Intrabodies can also betargeted to exert function in the cytosol. For example, cytosolicintrabodies are used to sequester factors within the cytosol, therebypreventing them from being transported to their natural cellulardestination.

In one embodiment, intrabodies are used to capture 98P4B6 in thenucleus, thereby preventing its activity within the nucleus. Nucleartargeting signals are engineered into such 98P4B6 intrabodies in orderto achieve the desired targeting. Such 98P4B6 intrabodies are designedto bind specifically to a particular 98P4B6 domain. In anotherembodiment, cytosolic intrabodies that specifically bind to a 98P4B6protein are used to prevent 98P4B6 from gaining access to the nucleus,thereby preventing it from exerting any biological activity within thenucleus (e.g., preventing 98P4B6 from forming transcription complexeswith other factors).

In order to specifically direct the expression of such intrabodies toparticular cells, the transcription of the intrabody is placed under theregulatory control of an appropriate tumor-specific promoter and/orenhancer. In order to target intrabody expression specifically toprostate, for example, the PSA promoter and/or promoter/enhancer can beutilized (See, for example, U.S. Pat. No. 5,919,652 issued 6 Jul. 1999).

XII.B.) Inhibition of 98P4B6 with Recombinant Proteins

In another approach, recombinant molecules bind to 98P4B6 and therebyinhibit 98P4B6 function. For example, these recombinant moleculesprevent or inhibit 98P4B6 from accessing/binding to its bindingpartner(s) or associating with other protein(s). Such recombinantmolecules can, for example, contain the reactive part(s) of a 98P4B6specific antibody molecule. In a particular embodiment, the 98P4B6binding domain of a 98P4B6 binding partner is engineered into a dimericfusion protein, whereby the fusion protein comprises two 98P4B6 ligandbinding domains linked to the Fc portion of a human IgG, such as humanIgG1. Such IgG portion can contain, for example, the CH2 and CH3 domainsand the hinge region, but not the CH1 domain. Such dimeric fusionproteins are administered in soluble form to patients suffering from acancer associated with the expression of 98P4B6, whereby the dimericfusion protein specifically binds to 98P4B6 and blocks 98P4B6interaction with a binding partner. Such dimeric fusion proteins arefurther combined into multimeric proteins using known antibody linkingtechnologies.

XII.C.) Inhibition of 98P4B6 Transcription or Translation

The present invention also comprises various methods and compositionsfor inhibiting the transcription of the 98P4B6 gene. Similarly, theinvention also provides methods and compositions for inhibiting thetranslation of 98P4B6 mRNA into protein.

In one approach, a method of inhibiting the transcription of the 98P4B6gene comprises contacting the 98P4B6 gene with a 98P4B6 antisensepolynucleotide. In another approach, a method of inhibiting 98P4B6 mRNAtranslation comprises contacting a 98P4B6 mRNA with an antisensepolynucleotide. In another approach, a 98P4B6 specific ribozyme is usedto cleave a 98P4B6 message, thereby inhibiting translation. Suchantisense and ribozyme based methods can also be directed to theregulatory regions of the 98P4B6 gene, such as 98P4B6 promoter and/orenhancer elements. Similarly, proteins capable of inhibiting a 98P4B6gene transcription factor are used to inhibit 98P4B6 mRNA transcription.The various polynucleotides and compositions useful in theaforementioned methods have been described above. The use of antisenseand ribozyme molecules to inhibit transcription and translation is wellknown in the art.

Other factors that inhibit the transcription of 98P4B6 by interferingwith 98P4B6 transcriptional activation are also useful to treat cancersexpressing 98P4B6. Similarly, factors that interfere with 98P4B6processing are useful to treat cancers that express 98P4B6. Cancertreatment methods utilizing such factors are also within the scope ofthe invention.

XII.D.) General Considerations for Therapeutic Strategies

Gene transfer and gene therapy technologies can be used to delivertherapeutic polynucleotide molecules to tumor cells synthesizing 98P4B6(i.e., antisense, ribozyme, polynucleotides encoding intrabodies andother 98P4B6 inhibitory molecules). A number of gene therapy approachesare known in the art. Recombinant vectors encoding 98P4B6 antisensepolynucleotides, ribozymes, factors capable of interfering with 98P4B6transcription, and so forth, can be delivered to target tumor cellsusing such gene therapy approaches.

The above therapeutic approaches can be combined with any one of a widevariety of surgical, chemotherapy or radiation therapy regimens. Thetherapeutic approaches of the invention can enable the use of reduceddosages of chemotherapy (or other therapies) and/or less frequentadministration, an advantage for all patients and particularly for thosethat do not tolerate the toxicity of the chemotherapeutic agent well.

The anti-tumor activity of a particular composition (e.g., antisense,ribozyme, intrabody), or a combination of such compositions, can beevaluated using various in vitro and in vivo assay systems. In vitroassays that evaluate therapeutic activity include cell growth assays,soft agar assays and other assays indicative of tumor promotingactivity, binding assays capable of determining the extent to which atherapeutic composition will inhibit the binding of 98P4B6 to a bindingpartner, etc.

In vivo, the effect of a 98P4B6 therapeutic composition can be evaluatedin a suitable animal model. For example, xenogenic prostate cancermodels can be used, wherein human prostate cancer explants or passagedxenograft tissues are introduced into immune compromised animals, suchas nude or SCID mice (Klein et al., 1997, Nature Medicine 3: 402-408).For example, PCT Patent Application WO98/16628 and U.S. Pat. No.6,107,540 describe various xenograft models of human prostate cancercapable of recapitulating the development of primary tumors,micrometastasis, and the formation of osteoblastic metastasescharacteristic of late stage disease. Efficacy can be predicted usingassays that measure inhibition of tumor formation, tumor regression ormetastasis, and the like.

In vivo assays that evaluate the promotion of apoptosis are useful inevaluating therapeutic compositions. In one embodiment, xenografts fromtumor bearing mice treated with the therapeutic composition can beexamined for the presence of apoptotic foci and compared to untreatedcontrol xenograft-bearing mice. The extent to which apoptotic foci arefound in the tumors of the treated mice provides an indication of thetherapeutic efficacy of the composition.

The therapeutic compositions used in the practice of the foregoingmethods can be formulated into pharmaceutical compositions comprising acarrier suitable for the desired delivery method. Suitable carriersinclude any material that when combined with the therapeutic compositionretains the anti-tumor function of the therapeutic composition and isgenerally non-reactive with the patient's immune system. Examplesinclude, but are not limited to, any of a number of standardpharmaceutical carriers such as sterile phosphate buffered salinesolutions, bacteriostatic water, and the like (see, generally,Remington's Pharmaceutical Sciences 16^(th) Edition, A. Osal., Ed.,1980).

Therapeutic formulations can be solubilized and administered via anyroute capable of delivering the therapeutic composition to the tumorsite. Potentially effective routes of administration include, but arenot limited to, intravenous, parenteral, intraperitoneal, intramuscular,intratumor, intradermal, intraorgan, orthotopic, and the like. Apreferred formulation for intravenous injection comprises thetherapeutic composition in a solution of preserved bacteriostatic water,sterile unpreserved water, and/or diluted in polyvinylchloride orpolyethylene bags containing 0.9% sterile Sodium Chloride for Injection,USP. Therapeutic protein preparations can be lyophilized and stored assterile powders, preferably under vacuum, and then reconstituted inbacteriostatic water (containing for example, benzyl alcoholpreservative) or in sterile water prior to injection.

Dosages and administration protocols for the treatment of cancers usingthe foregoing methods will vary with the method and the target cancer,and will generally depend on a number of other factors appreciated inthe art.

XIII.) Identification, Characterization and Use of Modulators of 98P4B6

Methods to Identify and Use Modulators

In one embodiment, screening is performed to identify modulators thatinduce or suppress a particular expression profile, suppress or inducespecific pathways, preferably generating the associated phenotypethereby. In another embodiment, having identified differentiallyexpressed genes important in a particular state; screens are performedto identify modulators that alter expression of individual genes, eitherincrease or decrease. In another embodiment, screening is performed toidentify modulators that alter a biological function of the expressionproduct of a differentially expressed gene. Again, having identified theimportance of a gene in a particular state, screens are performed toidentify agents that bind and/or modulate the biological activity of thegene product.

In addition, screens are done for genes that are induced in response toa candidate agent. After identifying a modulator (one that suppresses acancer expression pattern leading to a normal expression pattern, or amodulator of a cancer gene that leads to expression of the gene as innormal tissue) a screen is performed to identify genes that arespecifically modulated in response to the agent. Comparing expressionprofiles between normal tissue and agent-treated cancer tissue revealsgenes that are not expressed in normal tissue or cancer tissue, but areexpressed in agent treated tissue, and vice versa. These agent-specificsequences are identified and used by methods described herein for cancergenes or proteins. In particular these sequences and the proteins theyencode are used in marking or identifying agent-treated cells. Inaddition, antibodies are raised against the agent-induced proteins andused to target novel therapeutics to the treated cancer tissue sample.

Modulator-related Identification and Screening Assays:

Gene Expression-related Assays

Proteins, nucleic acids, and antibodies of the invention are used inscreening assays. The cancer-associated proteins, antibodies, nucleicacids, modified proteins and cells containing these sequences are usedin screening assays, such as evaluating the effect of drug candidates ona “gene expression profile,” expression profile of polypeptides oralteration of biological function. In one embodiment, the expressionprofiles are used, preferably in conjunction with high throughputscreening techniques to allow monitoring for expression profile genesafter treatment with a candidate agent (e.g., Davis, GF, et al, J BiolScreen 7:69 (2002); Zlokamik, et al., Science 279:84-8 (1998); Heid,Genome Res 6:986-94,1996).

The cancer proteins, antibodies, nucleic acids, modified proteins andcells containing the native or modified cancer proteins or genes areused in screening assays. That is, the present invention comprisesmethods for screening for compositions which modulate the cancerphenotype or a physiological function of a cancer protein of theinvention. This is done on a gene itself or by evaluating the effect ofdrug candidates on a “gene expression profile” or biological function.In one embodiment, expression profiles are used, preferably inconjunction with high throughput screening techniques to allowmonitoring after treatment with a candidate agent, see Zlokamik, supra.

A variety of assays are executed directed to the genes and proteins ofthe invention. Assays are run on an individual nucleic acid or proteinlevel. That is, having identified a particular gene as up regulated incancer, test compounds are screened for the ability to modulate geneexpression or for binding to the cancer protein of the invention.“Modulation” in this context includes an increase or a decrease in geneexpression. The preferred amount of modulation will depend on theoriginal change of the gene expression in normal versus tissueundergoing cancer, with changes of at least 10%, preferably 50%, morepreferably 100-300%, and in some embodiments 300-1000% or greater. Thus,if a gene exhibits a 4-fold increase in cancer tissue compared to normaltissue, a decrease of about four-fold is often desired; similarly, a10-fold decrease in cancer tissue compared to normal tissue a targetvalue of a 10-fold increase in expression by the test compound is oftendesired. Modulators that exacerbate the type of gene expression seen incancer are also useful, e.g., as an upregulated target in furtheranalyses.

The amount of gene expression is monitored using nucleic acid probes andthe quantification of gene expression levels, or, alternatively, a geneproduct itself is monitored, e.g., through the use of antibodies to thecancer protein and standard immunoassays. Proteomics and separationtechniques also allow for quantification of expression.

Expression Monitoring to Identify Compounds that Modify Gene Expression

In one embodiment, gene expression monitoring, i.e., an expressionprofile, is monitored simultaneously for a number of entities. Suchprofiles will typically involve one or more of the genes of FIG. 2. Inthis embodiment, e.g., cancer nucleic acid probes are attached tobiochips to detect and quantify cancer sequences in a particular cell.Alternatively, PCR can be used. Thus, a series, e.g., wells of amicrotiter plate, can be used with dispensed primers in desired wells. APCR reaction can then be performed and analyzed for each well.

Expression monitoring is performed to identify compounds that modify theexpression of one or more cancer-associated sequences, e.g., apolynucleotide sequence set out in FIG. 2. Generally, a test modulatoris added to the cells prior to analysis. Moreover, screens are alsoprovided to identify agents that modulate cancer, modulate cancerproteins of the invention, bind to a cancer protein of the invention, orinterfere with the binding of a cancer protein of the invention and anantibody or other binding partner.

In one embodiment, high throughput screening methods involve providing alibrary containing a large number of potential therapeutic compounds(candidate compounds). Such “combinatorial chemical libraries” are thenscreened in one or more assays to identify those library members(particular chemical species or subclasses) that display a desiredcharacteristic activity. The compounds thus identified can serve asconventional “lead compounds,” as compounds for screening, or astherapeutics.

In certain embodiments, combinatorial libraries of potential modulatorsare screened for an ability to bind to a cancer polypeptide or tomodulate activity. Conventionally, new chemical entities with usefulproperties are generated by identifying a chemical compound (called a“lead compound”) with some desirable property or activity, e.g.,inhibiting activity, creating variants of the lead compound, andevaluating the property and activity of those variant compounds. Often,high throughput screening (HTS) methods are employed for such ananalysis.

As noted above, gene expression monitoring is conveniently used to testcandidate modulators (e.g., protein, nucleic acid or small molecule).After the candidate agent has been added and the cells allowed toincubate for a period, the sample containing a target sequence to beanalyzed is, e.g., added to a biochip.

If required, the target sequence is prepared using known techniques. Forexample, a sample is treated to lyse the cells, using known lysisbuffers, electroporation, etc., with purification and/or amplificationsuch as PCR performed as appropriate. For example, an in vitrotranscription with labels covalently attached to the nucleotides isperformed. Generally, the nucleic acids are labeled with biotin-FITC orPE, or with cy3 or cy5.

The target sequence can be labeled with, e.g., a fluorescent, achemiluminescent, a chemical, or a radioactive signal, to provide ameans of detecting the target sequence's specific binding to a probe.The label also can be an enzyme, such as alkaline phosphatase orhorseradish peroxidase, which when provided with an appropriatesubstrate produces a product that is detected. Alternatively, the labelis a labeled compound or small molecule, such as an enzyme inhibitor,that binds but is not catalyzed or altered by the enzyme. The label alsocan be a moiety or compound, such as, an epitope tag or biotin whichspecifically binds to streptavidin. For the example of biotin, thestreptavidin is labeled as described above, thereby, providing adetectable signal for the bound target sequence. Unbound labeledstreptavidin is typically removed prior to analysis.

As will be appreciated by those in the art, these assays can be directhybridization assays or can comprise “sandwich assays”, which includethe use of multiple probes, as is generally outlined in U.S. Pat. Nos.5,681,702; 5,597,909; 5,545,730; 5,594,117; 5,591,584; 5,571,670;5,580,731; 5,571,670; 5,591,584; 5,624,802; 5,635,352; 5,594,118;5,359,100; 5,124,246; and 5,681,697. In this embodiment, in general, thetarget nucleic acid is prepared as outlined above, and then added to thebiochip comprising a plurality of nucleic acid probes, under conditionsthat allow the formation of a hybridization complex.

A variety of hybridization conditions are used in the present invention,including high, moderate and low stringency conditions as outlinedabove. The assays are generally run under stringency conditions whichallow formation of the label probe hybridization complex only in thepresence of target. Stringency can be controlled by altering a stepparameter that is a thermodynamic variable, including, but not limitedto, temperature, formamide concentration, salt concentration, chaotropicsalt concentration pH, organic solvent concentration, etc. Theseparameters may also be used to control non-specific binding, as isgenerally outlined in U.S. Pat. No. 5,681,697. Thus, it can be desirableto perform certain steps at higher stringency conditions to reducenon-specific binding.

The reactions outlined herein can be accomplished in a variety of ways.Components of the reaction can be added simultaneously, or sequentially,in different orders, with preferred embodiments outlined below. Inaddition, the reaction may include a variety of other reagents. Theseinclude salts, buffers, neutral proteins, e.g. albumin, detergents, etc.which can be used to facilitate optimal hybridization and detection,and/or reduce nonspecific or background interactions. Reagents thatotherwise improve the efficiency of the assay, such as proteaseinhibitors, nuclease inhibitors, anti-microbial agents, etc., may alsobe used as appropriate, depending on the sample preparation methods andpurity of the target. The assay data are analyzed to determine theexpression levels of individual genes, and changes in expression levelsas between states, forming a gene expression profile.

Biological Activity-related Assays

The invention provides methods identify or screen for a compound thatmodulates the activity of a cancer-related gene or protein of theinvention. The methods comprise adding a test compound, as definedabove, to a cell comprising a cancer protein of the invention. The cellscontain a recombinant nucleic acid that encodes a cancer protein of theinvention. In another embodiment, a library of candidate agents istested on a plurality of cells.

In one aspect, the assays are evaluated in the presence or absence orprevious or subsequent exposure of physiological signals, e.g. hormones,antibodies, peptides, antigens, cytokines, growth factors, actionpotentials, pharmacological agents including chemotherapeutics,radiation, carcinogenics, or other cells (i.e., cell-cell contacts). Inanother example, the determinations are made at different stages of thecell cycle process. In this way, compounds that modulate genes orproteins of the invention are identified. Compounds with pharmacologicalactivity are able to enhance or interfere with the activity of thecancer protein of the invention. Once identified, similar structures areevaluated to identify critical structural features of the compound.

In one embodiment, a method of modulating (e.g., inhibiting) cancer celldivision is provided; the method comprises administration of a cancermodulator. In another embodiment, a method of modulating (e.g.,inhibiting) cancer is provided; the method comprises administration of acancer modulator. In a further embodiment, methods of treating cells orindividuals with cancer are provided; the method comprisesadministration of a cancer modulator.

In one embodiment, a method for modulating the status of a cell thatexpresses a gene of the invention is provided. As used herein statuscomprises such art-accepted parameters such as growth, proliferation,survival, function, apoptosis, senescence, location, enzymatic activity,signal transduction, etc. of a cell. In one embodiment, a cancerinhibitor is an antibody as discussed above. In another embodiment, thecancer inhibitor is an antisense molecule. A variety of cell growth,proliferation, and metastasis assays are known to those of skill in theart, as described herein.

High Throughput Screening to Identify Modulators

The assays to identify suitable modulators are amenable to highthroughput screening. Preferred assays thus detect enhancement orinhibition of cancer gene transcription, inhibition or enhancement ofpolypeptide expression, and inhibition or enhancement of polypeptideactivity.

In one embodiment, modulators evaluated in high throughput screeningmethods are proteins, often naturally occurring proteins or fragments ofnaturally occurring proteins. Thus, e.g., cellular extracts containingproteins, or random or directed digests of proteinaceous cellularextracts, are used. In this way, libraries of proteins are made forscreening in the methods of the invention. Particularly preferred inthis embodiment are libraries of bacterial, fungal, viral, and mammalianproteins, with the latter being preferred, and human proteins beingespecially preferred. Particularly useful test compound will be directedto the class of proteins to which the target belongs, e.g., substratesfor enzymes, or ligands and receptors.

Use of Soft Agar Growth and Colony Formation to Identify andCharacterize Modulators

Normal cells require a solid substrate to attach and grow. When cellsare transformed, they lose this phenotype and grow detached from thesubstrate. For example, transformed cells can grow in stirred suspensionculture or suspended in semi-solid media, such as semi-solid or softagar. The transformed cells, when transfected with tumor suppressorgenes, can regenerate normal phenotype and once again require a solidsubstrate to attach to and grow. Soft agar growth or colony formation inassays are used to identify modulators of cancer sequences, which whenexpressed in host cells, inhibit abnormal cellular proliferation andtransformation. A modulator reduces or eliminates the host cells'ability to grow suspended in solid or semisolid media, such as agar.

Techniques for soft agar growth or colony formation in suspension assaysare described in Freshney, Culture of Animal Cells a Manual of BasicTechnique (3rd ed., 1994). See also, the methods section of Garkavtsevet al. (1996), supra.

Evaluation of Contact Inhibition and Growth Density Limitation toIdentify and Characterize Modulators

Normal cells typically grow in a flat and organized pattern in cellculture until they touch other cells. When the cells touch one another,they are contact inhibited and stop growing. Transformed cells, however,are not contact inhibited and continue to grow to high densities indisorganized foci. Thus, transformed cells grow to a higher saturationdensity than corresponding normal cells. This is detectedmorphologically by the formation of a disoriented monolayer of cells orcells in foci. Alternatively, labeling index with (³H)-thymidine atsaturation density is used to measure density limitation of growth,similarly an MTT or Alamar blue assay will reveal proliferation capacityof cells and the ability of modulators to affect same. See Freshney(1994), supra. Transformed cells, when transfected with tumor suppressorgenes, can regenerate a normal phenotype and become contact inhibitedand would grow to a lower density.

In this assay, labeling index with ³H)-thymidine at saturation densityis a preferred method of measuring density limitation of growth.Transformed host cells are transfected with a cancer-associated sequenceand are grown for 24 hours at saturation density in non-limiting mediumconditions. The percentage of cells labeling with (³H)-thymidine isdetermined by incorporated cpm.

Contact independent growth is used to identify modulators of cancersequences, which had led to abnormal cellular proliferation andtransformation. A modulator reduces or eliminates contact independentgrowth, and returns the cells to a normal phenotype.

Evaluation of Growth Factor or Serum Dependence to Identify andCharacterize Modulators

Transformed cells have lower serum dependence than their normalcounterparts (see, e.g., Temin, J. Natl. Cancer Inst. 37:167-175 (1966);Eagle et al., J. Exp. Med 131:836-879 (1970)); Freshney, supra. This isin part due to release of various growth factors by the transformedcells. The degree of growth factor or serum dependence of transformedhost cells can be compared with that of control. For example, growthfactor or serum dependence of a cell is monitored in methods to identifyand characterize compounds that modulate cancer-associated sequences ofthe invention.

Use of Tumor-specific Marker Levels to Identify and CharacterizeModulators

Tumor cells release an increased amount of certain factors (hereinafter“tumor specific markers”) than their normal counterparts. For example,plasminogen activator (PA) is released from human glioma at a higherlevel than from normal brain cells (see, e.g., Gullino, Angiogenesis,Tumor Vascularization, and Potential Interference with Tumor Growth, inBiological Responses in Cancer, pp. 178-184 (Mihich (ed.) 1985)).Similarly, Tumor Angiogenesis Factor (TAF) is released at a higher levelin tumor cells than their normal counterparts. See, e.g., Folkman,Angiogenesis and Cancer, Sem Cancer Biol. (1992)), while bFGF isreleased from endothelial tumors (Ensoli, B et al).

Various techniques which measure the release of these factors aredescribed in Freshney (1994), supra. Also, see, Unkless et al., J. Biol.Chem. 249:4295-4305 (1974); Strickland & Beers, J. Biol. Chem.251:5694-5702 (1976); Whur et al., Br. J. Cancer 42:305 312 (1980);Gullino, Angiogenesis, Tumor Vascularization, and Potential Interferencewith Tumor Growth, in Biological Responses in Cancer, pp. 178-184(Mihich (ed.) 1985); Freshney, Anticancer Res. 5:111-130 (1985). Forexample, tumor specific marker levels are monitored in methods toidentify and characterize compounds that modulate cancer-associatedsequences of the invention.

Invasiveness into Matrigel to Identify and Characterize Modulators

The degree of invasiveness into Matrigel or an extracellular matrixconstituent can be used as an assay to identify and characterizecompounds that modulate cancer associated sequences. Tumor cells exhibita positive correlation between malignancy and invasiveness of cells intoMatrigel or some other extracellular matrix constituent. In this assay,tumorigenic cells are typically used as host cells. Expression of atumor suppressor gene in these host cells would decrease invasiveness ofthe host cells. Techniques described in Cancer Res. 1999; 59:6010;Freshney (1994), supra, can be used. Briefly, the level of invasion ofhost cells is measured by using filters coated with Matrigel or someother extracellular matrix constituent. Penetration into the gel, orthrough to the distal side of the filter, is rated as invasiveness, andrated histologically by number of cells and distance moved, or byprelabeling the cells with ¹²⁵I and counting the radioactivity on thedistal side of the filter or bottom of the dish. See, e.g., Freshney(1984), supra.

Evaluation of Tumor Growth In Vivo to Identify and CharacterizeModulators

Effects of cancer-associated sequences on cell growth are tested intransgenic or immune-suppressed organisms. Transgenic organisms areprepared in a variety of art-accepted ways. For example, knock-outtransgenic organisms, e.g., mammals such as mice, are made, in which acancer gene is disrupted or in which a cancer gene is inserted.Knock-out transgenic mice are made by insertion of a marker gene orother heterologous gene into the endogenous cancer gene site in themouse genome via homologous recombination. Such mice can also be made bysubstituting the endogenous cancer gene with a mutated version of thecancer gene, or by mutating the endogenous cancer gene, e.g., byexposure to carcinogens.

To prepare transgenic chimeric animals, e.g., mice, a DNA construct isintroduced into the nuclei of embryonic stem cells. Cells containing thenewly engineered genetic lesion are injected into a host mouse embryo,which is re-implanted into a recipient female. Some of these embryosdevelop into chimeric mice that possess germ cells some of which arederived from the mutant cell line. Therefore, by breeding the chimericmice it is possible to obtain a new line of mice containing theintroduced genetic lesion (see, e.g., Capecchi et al., Science 244:1288(1989)). Chimeric mice can be derived according to U.S. Pat. No.6,365,797, issued 2 Apr. 2002; U.S. Pat. No. 6,107,540 issued 22 Aug.2000; Hogan et al., Manipulating the Mouse Embryo: A laboratory Manual,Cold Spring Harbor Laboratory (1988) and Teratocarcinomas and EmbryonicStem Cells: A Practical Approach, Robertson, ed., IRL Press, Washington,D.C., (1987).

Alternatively, various immune-suppressed or immune-deficient hostanimals can be used. For example, a genetically athymic “nude” mouse(see, e.g., Giovanella et al., J. Natl. Cancer Inst. 52:921 (1974)), aSCID mouse, a thymectomized mouse, or an irradiated mouse (see, e.g.,Bradley et al., Br. J. Cancer 38:263 (1978); Selby et al., Br. J. Cancer41:52 (1980)) can be used as a host. Transplantable tumor cells(typically about 10⁶ cells) injected into isogenic hosts produceinvasive tumors in a high proportion of cases, while normal cells ofsimilar origin will not. In hosts which developed invasive tumors, cellsexpressing cancer-associated sequences are injected subcutaneously ororthotopically. Mice are then separated into groups, including controlgroups and treated experimental groups) e.g. treated with a modulator).After a suitable length of time, preferably 4-8 weeks, tumor growth ismeasured (e.g., by volume or by its two largest dimensions, or weight)and compared to the control. Tumors that have statistically significantreduction (using, e.g., Student's T test) are said to have inhibitedgrowth.

In Vitro Assays to Identify and Characterize Modulators

Assays to identify compounds with modulating activity can be performedin vitro. For example, a cancer polypeptide is first contacted with apotential modulator and incubated for a suitable amount of time, e.g.,from 0.5 to 48 hours. In one embodiment, the cancer polypeptide levelsare determined in vitro by measuring the level of protein or mRNA. Thelevel of protein is measured using immunoassays such as Westernblotting, ELISA and the like with an antibody that selectively binds tothe cancer polypeptide or a fragment thereof. For measurement of mRNA,amplification, e.g., using PCR, LCR, or hybridization assays, e.g.,Northern hybridization, RNAse protection, dot blotting, are preferred.The level of protein or mRNA is detected using directly or indirectlylabeled detection agents, e.g., fluorescently or radioactively labelednucleic acids, radioactively or enzymatically labeled antibodies, andthe like, as described herein.

Alternatively, a reporter gene system can be devised using a cancerprotein promoter operably linked to a reporter gene such as luciferase,green fluorescent protein, CAT, or P-gal. The reporter construct istypically transfected into a cell. After treatment with a potentialmodulator, the amount of reporter gene transcription, translation, oractivity is measured according to standard techniques known to those ofskill in the art (Davis G F, supra; Gonzalez, J. & Negulescu, P. Curr.Opin. Biotechnol. 1998: 9:624).

As outlined above, in vitro screens are done on individual genes andgene products. That is, having identified a particular differentiallyexpressed gene as important in a particular state, screening ofmodulators of the expression of the gene or the gene product itself isperformed.

In one embodiment, screening for modulators of expression of specificgene(s) is performed. Typically, the expression of only one or a fewgenes is evaluated. In another embodiment, screens are designed to firstfind compounds that bind to differentially expressed proteins. Thesecompounds are then evaluated for the ability to modulate differentiallyexpressed activity. Moreover, once initial candidate compounds areidentified, variants can be further screened to better evaluatestructure activity relationships.

Binding Assays to Identify and Characterize Modulators

In binding assays in accordance with the invention, a purified orisolated gene product of the invention is generally used. For example,antibodies are generated to a protein of the invention, and immunoassaysare run to determine the amount and/or location of protein.Alternatively, cells comprising the cancer proteins are used in theassays.

Thus, the methods comprise combining a cancer protein of the inventionand a candidate compound such as a ligand, and determining the bindingof the compound to the cancer protein of the invention. Preferredembodiments utilize the human cancer protein; animal models of humandisease of can also be developed and used. Also, other analogousmammalian proteins also can be used as appreciated by those of skill inthe art. Moreover, in some embodiments variant or derivative cancerproteins are used.

Generally, the cancer protein of the invention, or the ligand, isnon-diffusibly bound to an insoluble support. The support can, e.g., beone having isolated sample receiving areas (a microtiter plate, anarray, etc.). The insoluble supports can be made of any composition towhich the compositions can be bound, is readily separated from solublematerial, and is otherwise compatible with the overall method ofscreening. The surface of such supports can be solid or porous and ofany convenient shape.

Examples of suitable insoluble supports include microtiter plates,arrays, membranes and beads. These are typically made of glass, plastic(e.g., polystyrene), polysaccharide, nylon, nitrocellulose, or Teflon™,etc. Microtiter plates and arrays are especially convenient because alarge number of assays can be carried out simultaneously, using smallamounts of reagents and samples. The particular manner of binding of thecomposition to the support is not crucial so long as it is compatiblewith the reagents and overall methods of the invention, maintains theactivity of the composition and is nondiffusable. Preferred methods ofbinding include the use of antibodies which do not sterically blockeither the ligand binding site or activation sequence when attaching theprotein to the support, direct binding to “sticky” or ionic supports,chemical crosslinking, the synthesis of the protein or agent on thesurface, etc. Following binding of the protein or ligand/binding agentto the support, excess unbound material is removed by washing. Thesample receiving areas may then be blocked through incubation withbovine serum albumin (BSA), casein or other innocuous protein or othermoiety.

Once a cancer protein of the invention is bound to the support, and atest compound is added to the assay. Alternatively, the candidatebinding agent is bound to the support and the cancer protein of theinvention is then added. Binding agents include specific antibodies,non-natural binding agents identified in screens of chemical libraries,peptide analogs, etc.

Of particular interest are assays to identify agents that have a lowtoxicity for human cells. A wide variety of assays can be used for thispurpose, including proliferation assays, cAMP assays, labeled in vitroprotein-protein binding assays, electrophoretic mobility shift assays,immunoassays for protein binding, functional assays (phosphorylationassays, etc.) and the like.

A determination of binding of the test compound (ligand, binding agent,modulator, etc.) to a cancer protein of the invention can be done in anumber of ways. The test compound can be labeled, and binding determineddirectly, e.g., by attaching all or a portion of the cancer protein ofthe invention to a solid support, adding a labeled candidate compound(e.g., a fluorescent label), washing off excess reagent, and determiningwhether the label is present on the solid support. Various blocking andwashing steps can be utilized as appropriate.

In certain embodiments, only one of the components is labeled, e.g., aprotein of the invention or ligands labeled. Alternatively, more thanone component is labeled with different labels, e.g., I¹²⁵, for theproteins and a fluorophor for the compound. Proximity reagents, e.g.,quenching or energy transfer reagents are also useful.

Competitive Binding to Identify and Characterize Modulators

In one embodiment, the binding of the “test compound” is determined bycompetitive binding assay with a “competitor.” The competitor is abinding moiety that binds to the target molecule (e.g., a cancer proteinof the invention). Competitors include compounds such as antibodies,peptides, binding partners, ligands, etc. Under certain circumstances,the competitive binding between the test compound and the competitordisplaces the test compound. In one embodiment, the test compound islabeled. Either the test compound, the competitor, or both, is added tothe protein for a time sufficient to allow binding. Incubations areperformed at a temperature that facilitates optimal activity, typicallybetween four and 40° C. Incubation periods are typically optimized,e.g., to facilitate rapid high throughput screening; typically betweenzero and one hour will be sufficient. Excess reagent is generallyremoved or washed away. The second component is then added, and thepresence or absence of the labeled component is followed, to indicatebinding.

In one embodiment, the competitor is added first, followed by the testcompound. Displacement of the competitor is an indication that the testcompound is binding to the cancer protein and thus is capable of bindingto, and potentially modulating, the activity of the cancer protein. Inthis embodiment, either component can be labeled. Thus, e.g., if thecompetitor is labeled, the presence of label in the post-test compoundwash solution indicates displacement by the test compound.Alternatively, if the test compound is labeled, the presence of thelabel on the support indicates displacement.

In an alternative embodiment, the test compound is added first, withincubation and washing, followed by the competitor. The absence ofbinding by the competitor indicates that the test compound binds to thecancer protein with higher affinity than the competitor. Thus, if thetest compound is labeled, the presence of the label on the support,coupled with a lack of competitor binding, indicates that the testcompound binds to and thus potentially modulates the cancer protein ofthe invention.

Accordingly, the competitive binding methods comprise differentialscreening to identity agents that are capable of modulating the activityof the cancer proteins of the invention. In this embodiment, the methodscomprise combining a cancer protein and a competitor in a first sample.A second sample comprises a test compound, the cancer protein, and acompetitor. The binding of the competitor is determined for bothsamples, and a change, or difference in binding between the two samplesindicates the presence of an agent capable of binding to the cancerprotein and potentially modulating its activity. That is, if the bindingof the competitor is different in the second sample relative to thefirst sample, the agent is capable of binding to the cancer protein.

Alternatively, differential screening is used to identify drugcandidates that bind to the native cancer protein, but cannot bind tomodified cancer proteins. For example the structure of the cancerprotein is modeled and used in rational drug design to synthesize agentsthat interact with that site, agents which generally do not bind tosite-modified proteins. Moreover, such drug candidates that affect theactivity of a native cancer protein are also identified by screeningdrugs for the ability to either enhance or reduce the activity of suchproteins.

Positive controls and negative controls can be used in the assays.Preferably control and test samples are performed in at least triplicateto obtain statistically significant results. Incubation of all samplesoccurs for a time sufficient to allow for the binding of the agent tothe protein. Following incubation, samples are washed free ofnon-specifically bound material and the amount of bound, generallylabeled agent determined. For example, where a radiolabel is employed,the samples can be counted in a scintillation counter to determine theamount of bound compound.

A variety of other reagents can be included in the screening assays.These include reagents like salts, neutral proteins, e.g. albumin,detergents, etc. which are used to facilitate optimal protein-proteinbinding and/or reduce non-specific or background interactions. Alsoreagents that otherwise improve the efficiency of the assay, such asprotease inhibitors, nuclease inhibitors, anti-microbial agents, etc.,can be used. The mixture of components is added in an order thatprovides for the requisite binding.

Use of Polynucleotides to Down-regulate or Inhibit a Protein of theInvention.

Polynucleotide modulators of cancer can be introduced into a cellcontaining the target nucleotide sequence by formation of a conjugatewith a ligand-binding molecule, as described in WO 91/04753. Suitableligand-binding molecules include, but are not limited to, cell surfacereceptors, growth factors, other cytokines, or other ligands that bindto cell surface receptors. Preferably, conjugation of the ligand bindingmolecule does not substantially interfere with the ability of the ligandbinding molecule to bind to its corresponding molecule or receptor, orblock entry of the sense or antisense oligonucleotide or its conjugatedversion into the cell. Alternatively, a polynucleotide modulator ofcancer can be introduced into a cell containing the target nucleic acidsequence, e.g., by formation of a polynucleotide-lipid complex, asdescribed in WO 90/10448. It is understood that the use of antisensemolecules or knock out and knock in models may also be used in screeningassays as discussed above, in addition to methods of treatment.

Inhibitory and Antisense Nucleotides

In certain embodiments, the activity of a cancer-associated protein isdown-regulated, or entirely inhibited, by the use of antisensepolynucleotide or inhibitory small nuclear RNA (snRNA), i.e., a nucleicacid complementary to, and which can preferably hybridize specificallyto, a coding mRNA nucleic acid sequence, e.g., a cancer protein of theinvention, mRNA, or a subsequence thereof. Binding of the antisensepolynucleotide to the mRNA reduces the translation and/or stability ofthe mRNA.

In the context of this invention, antisense polynucleotides can comprisenaturally occurring nucleotides, or synthetic species formed fromnaturally occurring subunits or their close homologs. Antisensepolynucleotides may also have altered sugar moieties or inter-sugarlinkages. Exemplary among these are the phosphorothioate and othersulfur containing species which are known for use in the art. Analogsare comprised by this invention so long as they function effectively tohybridize with nucleotides of the invention. See, e.g., IsisPharmaceuticals, Carlsbad, Calif.; Sequitor, Inc., Natick, Mass.

Such antisense polynucleotides can readily be synthesized usingrecombinant means, or can be synthesized in vitro. Equipment for suchsynthesis is sold by several vendors, including Applied Biosystems. Thepreparation of other oligonucleotides such as phosphorothioates andalkylated derivatives is also well known to those of skill in the art.

Antisense molecules as used herein include antisense or senseoligonucleotides. Sense oligonucleotides can, e.g., be employed to blocktranscription by binding to the anti-sense strand. The antisense andsense oligonucleotide comprise a single stranded nucleic acid sequence(either RNA or DNA) capable of binding to target mRNA (sense) or DNA(antisense) sequences for cancer molecules. Antisense or senseoligonucleotides, according to the present invention, comprise afragment generally at least about 12 nucleotides, preferably from about12 to 30 nucleotides. The ability to derive an antisense or a senseoligonucleotide, based upon a CDNA sequence encoding a given protein isdescribed in, e.g., Stein &Cohen (Cancer Res. 48:2659 (1988 and van derKrol et al. (BioTechniques 6:958 (1988)).

Ribozymes

In addition to antisense polynucleotides, ribozymes can be used totarget and inhibit transcription of cancer-associated nucleotidesequences. A ribozyme is an RNA molecule that catalytically cleavesother RNA molecules. Different kinds of ribozymes have been described,including group I ribozymes, hammerhead ribozymes, hairpin ribozymes,RNase P, and axhead ribozymes (see, e.g., Castanotto et al., Adv. inPharmacology 25: 289-317 (1994) for a general review of the propertiesof different ribozymes).

The general features of hairpin ribozymes are described, e.g., in Hampelet al., Nucl. Acids Res. 18:299-304 (1990); European Patent PublicationNo. 0360257; U.S. Pat. No. 5,254,678. Methods of preparing are wellknown to those of skill in the art (see, e.g., WO 94/26877; Ojwang etal., Proc. Natl. Acad. Sci. USA 90:6340-6344 (1993); Yamada et al.,Human Gene Therapy 1:39-45 (1994); Leavitt et al., Proc. Natl. Acad Sci.USA 92:699-703 (1995); Leavitt et al., Human Gene Therapy 5: 1151-120(1994); and Yamada et al., Virology 205: 121-126 (1994)).

Use of Modulators in Phenotypic Screening

In one embodiment, a test compound is administered to a population ofcancer cells, which have an associated cancer expression profile. By“administration” or “contacting” herein is meant that the modulator isadded to the cells in such a manner as to allow the modulator to actupon the cell, whether by uptake and intracellular action, or by actionat the cell surface. In some embodiments, a nucleic acid encoding aproteinaceous agent (i.e., a peptide) is put into a viral construct suchas an adenoviral or retroviral construct, and added to the cell, suchthat expression of the peptide agent is accomplished, e.g., PCTUS97/01019. Regulatable gene therapy systems can also be used. Once themodulator has been administered to the cells, the cells are washed ifdesired and are allowed to incubate under preferably physiologicalconditions for some period. The cells are then harvested and a new geneexpression profile is generated. Thus, e.g., cancer tissue is screenedfor agents that modulate, e.g., induce or suppress, the cancerphenotype. A change in at least one gene, preferably many, of theexpression profile indicates that the agent has an effect on canceractivity. Similarly, altering a biological function or a signalingpathway is indicative of modulator activity. By defining such asignature for the cancer phenotype, screens for new drugs that alter thephenotype are devised. With this approach, the drug target need not beknown and need not be represented in the original gene/proteinexpression screening platform, nor does the level of transcript for thetarget protein need to change. The modulator inhibiting function willserve as a surrogate marker

As outlined above, screens are done to assess genes or gene products.That is, having identified a particular differentially expressed gene asimportant in a particular state, screening of modulators of either theexpression of the gene or the gene product itself is performed.

Use of Modulators to Affect Peptides of the Invention

Measurements of cancer polypeptide activity, or of the cancer phenotypeare performed using a variety of assays. For example, the effects ofmodulators upon the function of a cancer polypeptide(s) are measured byexamining parameters described above. A physiological change thataffects activity is used to assess the influence of a test compound onthe polypeptides of this invention. When the functional outcomes aredetermined using intact cells or animals, a variety of effects can beassesses such as, in the case of a cancer associated with solid tumors,tumor growth, tumor metastasis, neovascularization, hormone release,transcriptional changes to both known and uncharacterized geneticmarkers (e.g., by Northern blots), changes in cell metabolism such ascell growth or pH changes, and changes in intracellular secondmessengers such as cGNIP.

Methods of Identifying Characterizing Cancer-associated Sequences

Expression of various gene sequences is correlated with cancer.Accordingly, disorders based on mutant or variant cancer genes aredetermined. In one embodiment, the invention provides methods foridentifying cells containing variant cancer genes, e.g., determining thepresence of, all or part, the sequence of at least one endogenous cancergene in a cell. This is accomplished using any number of sequencingtechniques. The invention comprises methods of identifying the cancergenotype of an individual, e.g., determining all or part of the sequenceof at least one gene of the invention in the individual. This isgenerally done in at least one tissue of the individual, e.g., a tissueset forth in Table I, and may include the evaluation of a number oftissues or different samples of the same tissue. The method may includecomparing the sequence of the sequenced gene to a known cancer gene,i.e., a wild-type gene to determine the presence of family members,homologies, mutations or variants. The sequence of all or part of thegene can then be compared to the sequence of a known cancer gene todetermine if any differences exist. This is done using any number ofknown homology programs, such as BLAST, Bestfit, etc. The presence of adifference in the sequence between the cancer gene of the patient andthe known cancer gene correlates with a disease state or a propensityfor a disease state, as outlined herein.

In a preferred embodiment, the cancer genes are used as probes todetermine the number of copies of the cancer gene in the genome. Thecancer genes are used as probes to determine the chromosomallocalization of the cancer genes. Information such as chromosomallocalization finds use in providing a diagnosis or prognosis inparticular when chromosomal abnormalities such as translocations, andthe like are identified in the cancer gene locus.

XIV.) Kits/Articles of Manufacture

For use in the diagnostic and therapeutic applications described herein,kits are also within the scope of the invention. Such kits can comprisea carrier, package or container that is compartmentalized to receive oneor more containers such as vials, tubes, and the like, each of thecontainer(s) comprising one of the separate elements to be used in themethod. For example, the container(s) can comprise a probe that is orcan be detectably labeled. Such probe can be an antibody orpolynucleotide specific for a FIG. 2-related protein or a FIG. 2 gene ormessage, respectively. Where the method utilizes nucleic acidhybridization to detect the target nucleic acid, the kit can also havecontainers containing nucleotide(s) for amplification of the targetnucleic acid sequence and/or a container comprising a reporter-means,such as a biotin-binding protein, such as avidin or streptavidin, boundto a reporter molecule, such as an enzymatic, florescent, orradioisotope label. The kit can include all or part of the amino acidsequences in FIG. 2 or FIG. 3 or analogs thereof, or a nucleic acidmolecules that encodes such amino acid sequences.

The kit of the invention will typically comprise the container describedabove and one or more other containers comprising materials desirablefrom a commercial and user standpoint, including buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use.

A label can be present on the container to indicate that the compositionis used for a specific therapy or non-therapeutic application, such as adiagnostic or laboratory application, and can also indicate directionsfor either in vivo or in vitro use, such as those described herein.Directions and or other information can also be included on an insert(s)or label(s) which is included with or on the kit.

The terms “kit” and “article of manufacture” can be used as synonyms.

In another embodiment of the invention, an article(s) of manufacturecontaining compositions, such as amino acid sequence(s), smallmolecule(s), nucleic acid sequence(s), and/or antibody(s), e.g.,materials useful for the diagnosis, prognosis, prophylaxis and/ortreatment of neoplasias of tissues such as those set forth in Table I isprovided. The article of manufacture typically comprises at least onecontainer and at least one label. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers can beformed from a variety of materials such as glass or plastic. Thecontainer can hold amino acid sequence(s), small molecule(s), nucleicacid sequence(s), and/or antibody(s), in one embodiment the containerholds a polynucleotide for use in examining the mRNA expression profileof a cell, together with reagents used for this purpose.

The container can alternatively hold a composition which is effectivefor treating, diagnosis, prognosing or prophylaxing a condition and canhave a sterile access port (for example the container can be anintravenous solution bag or a vial having a stopper pierceable by ahypodermic injection needle). The active agents in the composition canbe an antibody capable of specifically binding 98P4B6 and modulating thefunction of 98P4B6.

The label can be on or associated with the container. A label a can beon a container when letters, numbers or other characters forming thelabel are molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Thelabel can indicate that the composition is used for diagnosing,treating, prophylaxing or prognosing a condition, such as a neoplasia ofa tissue set forth in Table I. The article of manufacture can furthercomprise a second container comprising a pharmaceutically-acceptablebuffer, such as phosphate-buffered saline, Ringer's solution and/ordextrose solution. It can further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, stirrers, needles, syringes, and/or package inserts withindications and/or instructions for use.

EXAMPLES

Various aspects of the invention are further described and illustratedby way of the several examples that follow, none of which are intendedto limit the scope of the invention.

Example 1 SSH-Generated Isolation of cDNA Fragment of the 98P4B6 Gene

To isolate genes that are over-expressed in prostate cancer we used theSuppression Subtractive Hybridization (SSH) procedure using cDNA derivedfrom prostate tissues. The 98P4B6 SSH cDNA sequence was derived fromnormal prostate minus LAPC-4AD prostate xenograft cDNAs. The 98P4B6 cDNAwas identified as highly expressed in prostate cancer.

Materials and Methods

Human Tissues:

The patient cancer and normal tissues were purchased from differentsources such as the NDRI (Philadelphia, Pa.). mRNA for some normaltissues were purchased from Clontech, Palo Alto, Calif.

RNA Isolation:

Tissues were homogenized in Trizol reagent (Life Technologies, GibcoBRL) using 10 ml/g tissue isolate total RNA. Poly A RNA was purifiedfrom total RNA using Qiagen's Oligotex mRNA Mini and Midi kits. Totaland mRNA were quantified by spectrophotometric analysis (O.D. 260/280nm) and analyzed by gel electrophoresis.

Oligonucleotides:

The following HPLC purified oligonucleotides were used.

DPNCDN (cDNA synthesis primer): (SEQ ID NO: 101) 5′TTTTGATCAAGCTT₃₀3′Adaptor 1: (SEQ ID NO: 102)5′CTAATACGACTCACTATAGGGCTCGAGCGGCCGCCCGGGCAG3′ (SEQ ID NO: 103)3′GGCCCGTCCTAG5′ Adaptor 2: (SEQ ID NO: 104)5′GTAATACGACTCACTATAGGGCAGCGTGGTCGCGGCCGAG3′ (SEQ ID NO: 105)3′CGGCTCCTAG5′ PCR primer 1: (SEQ ID NO: 106) 5′CTAATACGACTCACTATAGGGC3′Nested primer (NP)1: (SEQ ID NO: 107) 5′TCGAGCGGCCGCCCGGGCAGGA3′ Nestedprimer (NP)2: (SEQ ID NO: 108) 5′AGCGTGGTCGCGGCCGAGGA3′

Suppression Subtractive Hybridization:

Suppression Subtractive Hybridization (SSH) was used to identify cDNAscorresponding to genes that may be differentially expressed in prostatecancer. The SSH reaction utilized cDNA from prostate cancer xenograftand normal tissues.

The gene 98P4B6 sequence was derived from normal prostate tissue minusprostate cancer xenograft LAPC-4AD cDNA subtraction. The SSH DNAsequence (FIG. 1) was identified.

The cDNA derived from LAPC-4AD was used as the source of the “driver”cDNA, while the cDNA from normal prostate was used as the source of the“tester” cDNA. Double stranded cDNAs corresponding to tester and drivercDNAs were synthesized from 2 μg of poly(A), RNA isolated from therelevant tissue, as described above, using CLONTECH's PCR-Select cDNASubtraction Kit and 1 ng of oligonucleotide DPNCDN as primer. First- andsecond-strand synthesis were carried out as described in the Kit's usermanual protocol (CLONTECH Protocol No. PT1117-1, Catalog No. K1804-1).The resulting cDNA was digested with Dpn II for 3 hrs at 37° C. DigestedcDNA was extracted with phenol/chloroform (1:1) and ethanolprecipitated.

Driver cDNA was generated by combining in a 1:1 ratio Dpn II digestedcDNA from the relevant tissue source (see above) with digested cDNAsderived from normal tissue.

Tester cDNA was generated by diluting 1 μl of Dpn II digested cDNA fromthe relevant tissue source (see above) (400 ng) in 5 μl of water. Thediluted cDNA (2 μl, 160 ng) was then ligated to 2 μl of Adaptor 1 andAdaptor 2 (10 μM), in separate ligation reactions, in a total volume of10 μl at 16° C. overnight, using 400 u of T4 DNA ligase (CLONTECH).Ligation was terminated with 1 μl of 0.2 M EDTA and heating at 72° C.for 5 min.

The first hybridization was performed by adding 1.5 1I (600 ng) ofdriver cDNA to each of two tubes containing 1.5 μl (20 ng) Adaptor 1-and Adaptor 2-ligated tester cDNA. In a final volume of 4 μl, thesamples were overlaid with mineral oil, denatured in an MJ Researchthermal cycler at 98° C. for 1.5 minutes, and then were allowed tohybridize for 8 hrs at 68° C. The two hybridizations were then mixedtogether with an additional 1 μl of fresh denatured driver cDNA and wereallowed to hybridize overnight at 68° C. The second hybridization wasthen diluted in 200 μl of 20 mM Hepes, pH 8.3, 50 mM NaCl, 0.2 mM EDTA,heated at 70° C. for 7 min. and stored at −20° C.

PCR Amplification, Cloning and Sequencing of Gene Fragments Generatedfrom SSH:

To amplify gene fragments resulting from SSH reactions, two PCRamplifications were performed. In the primary PCR reaction 1 μl of thediluted final hybridization mix was added to 1 μl of PCR primer 1 (10μM), 0.5 μl dNTP mix (10 μM), 2.5 μl 10×reaction buffer (CLONTECH) and0.5 μl 50×Advantage cDNA polymerase Mix (CLONTECH) in a final volume of25 μl. PCR 1 was conducted using the following conditions: 75° C. for 5min., 94° C. for 25 sec., then 27 cycles of 94° C. for 10 sec, 66° C.for 30 sec, 72° C. for 1.5 min. Five separate primary PCR reactions wereperformed for each experiment. The products were pooled and diluted 1:10with water. For the secondary PCR reaction, 1 μl from the pooled anddiluted primary PCR reaction was added to the same reaction mix as usedfor PCR 1, except that primers NP1 and NP2 (10 μM) were used instead ofPCR primer 1. PCR 2 was performed using 10-12 cycles of 94° C. for 10sec, 68° C. for 30 sec, and 72° C. for 1.5 minutes. The PCR productswere analyzed using 2% agarose gel electrophoresis.

The PCR products were inserted into pCR2.1 using the T/A vector cloningkit (Invitrogen). Transformed E. coli were subjected to blue/white andampicillin selection. White colonies were picked and arrayed into 96well plates and were grown in liquid culture overnight. To identifyinserts, PCR amplification was performed on 1 ul of bacterial cultureusing the conditions of PCR1 and NP1 and NP2 as primers. PCR productswere analyzed using 2% agarose gel electrophoresis.

Bacterial clones were stored in 20% glycerol in a 96 well format.Plasmid DNA was prepared, sequenced, and subjected to nucleic acidhomology searches of the GenBank, dBest, and NCI-CGAP databases.

RT-PCR Expression Analysis:

First strand cDNAs can be generated from 1 μg of mRNA with oligo(dT)12-18 priming using the Gibco-BRL Superscript Preamplificationsystem. The manufacturer's protocol was used which included anincubation for 50 min at 42° C. with reverse transcriptase followed byRNAse H treatment at 37° C. for 20 min. After completing the reaction,the volume can be increased to 200 μl with water prior to normalization.First strand cDNAs from 16 different normal human tissues can beobtained from Clontech.

Normalization of the first strand cDNAs from multiple tissues wasperformed by using the primers 5′atatcgccgcgctcgtcgtcgacaa3′ (SEQ ID NO:109) and 5′agccacacgcagctcattgtagaagg 3′ (SEQ ID NO: 110) to amplifyβ-actin. First strand cDNA (5 μl) were amplified in a total volume of 50μl containing 0.4 μM primers, 0.2 μM each dNTPs, 1×PCR buffer (Clontech,10 mM Tris-HCl₂, 1.5 mM MgCl₂, 50 mM KCl, pH8.3) and 1X Klentaq DNApolymerase (Clontech). Five μl of the PCR reaction can be removed at 18,20, and 22 cycles and used for agarose gel electrophoresis. PCR wasperformed using an MJ Research thermal cycler under the followingconditions: Initial denaturation can be at 94° C. for 15 sec, followedby a 18, 20, and 22 cycles of 94° C. for 15, 65° C. for 2 min, 72° C.for 5 sec. A final extension at 72° C. was carried out for 2 min. Afteragarose gel electrophoresis, the band intensities of the 283 bp β-actinbands from multiple tissues were compared by visual inspection. Dilutionfactors for the first strand cDNAs were calculated to result in equalβ-actin band intensities in all tissues after 22 cycles of PCR. Threerounds of normalization can be required to achieve equal bandintensities in all tissues after 22 cycles of PCR.

To determine expression levels of the 98P4B6 gene, 5 μl of normalizedfirst strand cDNA were analyzed by PCR using 26, and 30 cycles ofamplification. Semi-quantitative expression analysis can be achieved bycomparing the PCR products at cycle numbers that give light bandintensities. The primers used for RT-PCR were designed using the 98P4B6SSH sequence and are listed below:

98P4B6.1 5′-GACTGAGCTGGAACTGGAATTTGT-3′ (SEQ ID NO: 111) 98P4B6.25′-TTTGAGGAGACTTCATCTCACTGG-3′ (SEQ ID NO: 112)

Example 2 Isolation of Full Length 98P4B6 Encoding cDNA

The 98P4B6 SSH cDNA sequence was derived from a substracton consistingof normal prostate minus prostate cancer xenograft. The SSH cDNAsequence (FIG. 1) was designated 98P4B6.

The 98P4B6 SSH DNA sequence of 183 bp is shown in FIG. 1. Full-length98P4B6 v.1 (clone GTD3) of 2453 bp was cloned from prostate cDNAlibrary, revealing an ORF of 454 amino acids (FIG. 2 and FIG. 3). 98P4B6v.6 was also cloned from normal prostate library. Other variants of98P4B6 were also identified and these are listed in FIGS. 2 and 3.

98P4B6 v.2, v.3, v.4, v.5, v.6, v.7 and v.8 are splice variants of98P4B6 v.1. 98P4B6 v.9 through v.19 are SNP variants and differ from v.1by one amino acid. 98P4B6 v.20 through v.24 are SNP variants of v.7.98P4B6 v.25 through v.38 are SNP variants of v.8. Though these SNPvariants were shown separately, they could also occur in anycombinations and in any transcript variants.

Example 3 Chromosomal Mapping of 98P4B6

Chromosomal localization can implicate genes in disease pathogenesis.Several chromosome mapping approaches are available includingfluorescent in situ hybridization (FISH), human/hamster radiation hybrid(RH) panels (Walter et al., 1994; Nature Genetics 7:22; ResearchGenetics, Huntsville Ala.), human-rodent somatic cell hybrid panels suchas is available from the Cornell Institute (Camden, N.J.), and genomicviewers utilizing BLAST homologies to sequenced and mapped genomicclones (NCBI, Bethesda, Md.).

98P4B6 maps to chromosome 7q21 using 98P4B6 sequence and the NCBI BLASTtool.

Example 4 Expression Analysis of 98P4B6

Expression analysis by RT-PCR demonstrated that 98P4B6 is stronglyexpressed in prostate cancer patient specimens (FIG. 14). First strandcDNA was generated from normal stomach, normal brain, normal heart,normal liver, normal skeletal muscle, normal testis, normal prostate,normal bladder, normal kidney, normal colon, normal lung, normalpancreas, and a pool of cancer specimens from prostate cancer patients,bladder cancer patients, kidney cancer patients, colon cancer patients,lung cancer patients, pancreas cancer patients, and a pool of 2 patientprostate metastasis to lymph node. Normalization was performed by PCRusing primers to actin. Semi-quantitative PCR, using primers directed to98P4B6 v.1, v.13, or/and v.14 (A), or directed specifically to thesplice variants 98P4B6 v.6 and v.8 (B), was performed at 26 and 30cycles of amplification. Samples were run on an agarose gel, and PCRproducts were quantitated using the Alphalmager software. Results showstrong expression of 98P4B6 and its splice variants v.6 and v.8 innormal prostate and in prostate cancer. Expression was also detected inbladder cancer, kidney cancer, colon cancer, lung cancer, pancreascancer, breast cancer, cancer metastasis as well as in the prostatecancer metastasis to lymph node specimens, compared to all normaltissues tested. As noted below, e.g., in Example 6, as 98P4B6 v. 1 is inexpressed in cancer tissues such as those listed in Table 1, the otherprotein-encoding 98P4B6 variants are expressed in these tissues as well;this principle is corroborated by data in (FIG. 14) for the proteinsherein designated 98P4B6 v.6 or v.8 is found, e.g., in prostate, lung,ovary, bladder, breast, colon, kidney and pancreas, cancers, as well asin the literature (Porkka et al., Lab Invest, 2002 and Korkmaz et al.,JBC, 2002) where the protein 98P4B6 v.8 is identified in normal prostateand prostate cancer.

When the genomic region to which a gene maps is modulated in aparticular cancer, the alternative transcripts or splice variants of thegene are modulated as well. Disclosed herein is that 98P4B6 has aparticular expression profile related to cancer. Alternative transcriptsand splice variants of 98P4B6 are also involved in cancers in the sameor additional tissues, thus serving as tumor-associatedmarkers/antigens.

Expression of 98P4B6 v.1, v.13, and/or v.14 was detected in prostate,lung, ovary, bladder, cervix, uterus and pancreas cancer patientspecimens (FIG. 15). First strand cDNA was prepared from a panel ofpatient cancer specimens. Normalization was performed by PCR usingprimers to actin. Semi-quantitative PCR, using primers to 98P4B6, wasperformed at 26 and 30 cycles of amplification. Samples were run on anagarose gel, and PCR products were quantitated using the Alphalmagersoftware. Expression was recorded as absent, low, medium or strong.Results show expression of 98P4B6 in the majority of all patient cancerspecimens tested.

FIG. 16 shows that 98P4B6 is expressed in stomach cancer patientspecimens. (A) RNA was extracted from normal stomach (N) and from 10different stomach cancer patient specimens (T). Northern blot with 10 μgof total RNA/lane was probed with 98P4B6 sequence. Results show strongexpression of 98P4B6 in the stomach tumor tissues and lower expressionin normal stomach. The lower panel represents ethidium bromide stainingof the blot showing quality of the RNA samples. (B) Expression of 98P4B6was assayed in a panel of human stomach cancers (T) and their respectivematched normal tissues (N) on RNA dot blots. 98P4B6 was detected in 7out of 8 stomach tumors but not in the matched normal tissues.

Example 5 Transcript Variants of 98P4B6

Transcript variants are variants of mature mRNA from the same gene whicharise by alternative transcription or alternative splicing. Alternativetranscripts are transcripts from the same gene but start transcriptionat different points. Splice variants are mRNA variants spliceddifferently from the same transcript. In eukaryotes, when a multi-exongene is transcribed from genomic DNA, the initial RNA is spliced toproduce functional mRNA, which has only exons and is used fortranslation into an amino acid sequence. Accordingly, a given gene canhave zero to many alternative transcripts and each transcript can havezero to many splice variants. Each transcript variant has a unique exonmakeup, and can have different coding and/or non-coding (5′ or 3′ end)portions, from the original transcript. Transcript variants can code forsimilar or different proteins with the same or a similar function or canencode proteins with different functions, and can be expressed in thesame tissue at the same time or in different tissues at the same time orin the same tissue at different times or in different tissues atdifferent times. Proteins encoded by transcript variants can havesimilar or different cellular or extracellular localizations, e.g.,secreted versus intracellular.

Transcript variants are identified by a variety of art-accepted methods.For example, alternative transcripts and splice variants are identifiedby full-length cloning experiment, or by use of full-length transcriptand EST sequences. First, all human ESTs were grouped into clusterswhich show direct or indirect identity with each other. Second, ESTs inthe same cluster were further grouped into sub-clusters and assembledinto a consensus sequence. The original gene sequence is compared to theconsensus sequence(s) or other full-length sequences. Each consensussequence is a potential splice variant for that gene. Even when avariant is identified that is not a full-length clone, that portion ofthe variant is very useful for antigen generation and for furthercloning of the full-length splice variant, using techniques known in theart.

Moreover, computer programs are available in the art that identifytranscript variants based on genomic sequences. Genomic-based transcriptvariant identification programs include FgenesH (A. Salamov and V.Solovyev, “Ab initio gene finding in Drosophila genomic DNA,” GenomeResearch. 2000 April; 10(4):516-22); Grail and GenScan. For a generaldiscussion of splice variant identification protocols see., e.g.,Southan, C., A genomic perspective on human proteases, FEBS Lett. 2001Jun. 8; 498(2-3):214-8; de Souza, S. J., et al., Identification of humanchromosome 22 transcribed sequences with ORF expressed sequence tags,Proc. Natl Acad Sci USA. 2000 Nov. 7; 97(23):12690-3.

To further confirm the parameters of a transcript variant, a variety oftechniques are available in the art, such as full-length cloning,proteomic validation, PCR-based validation, and 5′ RACE validation, etc.(see e.g., Proteomic Validation: Brennan, S. O., et al., Albumin bankspeninsula: a new termination variant characterized by electrospray massspectrometry, Biochem Biophys Acta. 1999 Aug. 17;1433(1-2):321-6;Ferranti P, et al., Differential splicing of pre-messenger RNA producesmultiple forms of mature caprine alpha(s1)-casein, Eur J Biochem. 1997Oct. 1;249(1):1-7. For PCR-based Validation: Wellmann S, et al.,Specific reverse transcription-PCR quantification of vascularendothelial growth factor (VEGF) splice variants by LightCyclertechnology, Clin Chem. 2001 April;47(4):654-60; Jia, H. P., et al.,Discovery of new human beta-defensins using a genomics-based approach,Gene. 2001 Jan. 24; 263(1-2):211-8. For PCR-based and 5′ RACEValidation: Brigle, K. E., et al., Organization of the murine reducedfolate carrier gene and identification of variant splice forms, BiochemBiophys Acta. 1997 Aug. 7; 1353(2): 191-8).

It is known in the art that genomic regions are modulated in cancers.Recently, Porkka et al. (2002) reported that transcript variants ofSTEAP2 were expressed and were found in both normal and malignantprostate tissue (Porkka, K. P., et al. Cloning and characterization of anovel six-transmembrane protein STEAP2, expressed in normal andmalignant prostate. Laboratory Investigation 2002 November;82(11):1573-1582). Another group of scientists also reported thattranscript variants of STEAP2 (98P4B6 v.6 herein) also were expressedsignificantly higher in prostate cancer than normal prostate (Korkmaz,K. S., et al. Molecular cloning and characterization of STAMP1, a highlyprostate-specific six transmembrane protein that is overexpressed inprostate cancer. The Journal of Biological Chemistry. 2002 September277(39):36689-36696.). When the genomic region to which a gene maps ismodulated in a particular cancer, the alternative transcripts or splicevariants of the gene are modulated as well. Disclosed herein is that98P4B6 has a particular expression profile related to cancer.Alternative transcripts and splice variants of 98P4B6 are also involvedin cancers in the same or additional tissues, thus serving astumor-associated markers/antigens.

Using the full-length gene and EST sequences, seven transcript variantswere identified, designated as 98P4B6 v.2, v.3, v.4, v.5, v.6, v.7 andv.8, as shown in FIG. 12. The boundaries of exons in the originaltranscript, 98P4B6 v.1 were shown in Table LI. The first 22 bases of v.1were not in the nearby 5′ region of v.1 on the current assembly of thehuman genome. Compared with 98P4B6 v.1, variant v.2 was a single exontranscript whose 3′ portion was the same as the last exon of v.1. Thefirst two exons of v.3 were in intron 1 of v. 1. Variants v.4, v.5, andv.6 spliced out 224-334 in the first exon of v.1. In addition, v.5spliced out exon 5 while v.6 spliced out exon 6 but extended exon 5 ofv.1. Variant v.7 used alternative transcription start and different 3′exons. Variant v.8 extended 5′ end and kept the whole intron 5 of v.1.Theoretically, each different combination of exons in spatial order,e.g. exons 2 and 3, is a potential splice variant.

Tables LII through LV are set forth on a variant-by-variant basis.Tables LII(a)-(g) show the nucleotide sequence of the transcriptvariant. Tables LII (a)-(g) show the alignment of the transcript variantwith the nucleic acid sequence of 98P4B6 v.1. Tables LIV(a)-(g) lay outthe amino acid translation of the transcript variant for the identifiedreading frame orientation. Tables LV(a)-(g) display alignments of theamino acid sequence encoded by the splice variant with that of 98P4B6v.1. Additionally, single nucleotide polymorphisms (SNP) are noted inthe alignment.

Example 6 Single Nucleotide Polymorphisms of 98P4B6

A Single Nucleotide Polymorphism (SNP) is a single base pair variationin a nucleotide sequence at a specific location. At any given point ofthe genome, there are four possible nucleotide base pairs: A/T, C/G, G/Cand T/A. Genotype refers to the specific base pair sequence of one ormore locations in the genome of an individual. Haplotype refers to thebase pair sequence of more than one location on the same DNA molecule(or the same chromosome in higher organisms), often in the context ofone gene or in the context of several tightly linked genes. SNP thatoccurs on a cDNA is called cSNP. This cSNP may change amino acids of theprotein encoded by the gene and thus change the functions of theprotein. Some SNP cause inherited diseases; others contribute toquantitative variations in phenotype and reactions to environmentalfactors including diet and drugs among individuals. Therefore, SNPand/or combinations of alleles (called haplotypes) have manyapplications, including diagnosis of inherited diseases, determinationof drug reactions and dosage, identification of genes responsible fordiseases, and analysis of the genetic relationship between individuals(P. Nowotny, J. M. Kwon and A. M. Goate, a “SNP analysis to dissecthuman traits,” Curr. Opin. Neurobiol. 2001 October; 11 (5):637-641; M.Pirmohamed and B. K. Park, “Genetic susceptibility to adverse drugreactions,” Trends Pharmacol. Sci. 2001 June; 22(6):298-305; J. H.Riley, C. J. Allan, E. Lai and A. Roses, “The use of single nucleotidepolymorphisms in the isolation of common disease genes,”Pharmacogenomics. 2000 February; 1(1):3947; R. Judson, J. C. Stephensand A. Windemuth, “The predictive power of haplotypes in clinicalresponse,” Pharmacogenomics. 2000 February; 1(1):15-26).

SNP are identified by a variety of art-accepted methods (P. Bean, “Thepromising voyage of SNP target discovery,” Am. Clin. Lab. 2001October-November; 20(9):18-20; K. M. Weiss, “In search of humanvariation,” Genome Res. 1998 July; 8(7):691-697; M. M. She, “Enablinglarge-scale pharmacogenetic studies by high-throughput mutationdetection and genotyping technologies,” Clin. Chem. 2001 Feb;47(2):164-172). For example, SNP can be identified by sequencing DNAfragments that show polymorphism by gel-based methods such asrestriction fragment length polymorphism (RFLP) and denaturing gradientgel electrophoresis (DGGE). They can also be discovered by directsequencing of DNA samples pooled from different individuals or bycomparing sequences from different DNA samples. With the rapidaccumulation of sequence data in public and private databases, one candiscover SNP by comparing sequences using computer programs (Z. Gu, L.Hillier and P. Y. Kwok, “Single nucleotide polymorphism hunting incyberspace,” Hum. Mutat. 1998; 12(4):221-225). SNP can be verified andgenotype or haplotype of an individual can be determined by a variety ofmethods including direct sequencing and high throughput microarrays (P.Y. Kwok, “Methods for genotyping single nucleotide polymorphisms,” Annu.Rev. Genomics Hum. Genet. 2001; 2:235-258; M. Kokoris, K. Dix, K.Moynihan, J. Mathis, B. Erwin, P. Grass, B. Hines and A. Duesterhoeft,“High-throughput SNP genotyping with the Masscode system,” Mol. Diagn.2000 December; 5(4):329-340).

Using the methods described above, eleven SNP were identified in theoriginal transcript, 98P4B6 v.1, at positions 46 (A/G), 179 (CfT), 180(A/G), 269 (A/G), 404 (GIT), 985 (CIT), 1170 (T/C), 1497 (ANG), 1746(T/G), 2046 (T/G) and 2103 (T/C). The transcripts or proteins withalternative allele were designated as variant 98P4B6 v.9 through v. 19,as shown in FIG. 10 a. FIG. 11 shows the schematic alignment of proteinvariants, corresponding to nucleotide variants. Nucleotide variants thatcode for the same amino acid sequence as v.1 are not shown in FIG. 11.These alleles of the SNP, though shown separately here, can occur indifferent combinations (haplotypes) and in any one of the transcriptvariants (such as 98P4B6 v.5) that contains the site of the SNP. Inaddition, there were SNP in other transcript variants in regions notshared with v.1. For example, there were fourteen SNP in the fifthintron of v.1, which was part of transcript variants v.2, v.6 and v.8.These SNP are shown in FIG. 10c and listed as following (numbersrelative v.8): 1760 (G/A), 1818 (GIT), 1870 (CIT), 2612 (T/C), 2926(T/A), 4241 (T/A), 4337 (AIG), 4338 (A/C), 4501 (A/G), 4506 (CIT), 5434(C/A), 5434 (C/G), 5434 (CIT) and 5589 (C/A). FIG. 1Ob shows the SNP inthe unique regions of transcript variant v.7: 1956 (A/C), 1987 (T/A),2010 (G/C), 2010 (G/T) and 2059 (G/A) (numbers correspond to nucleotidesequence of v.7).

Example 7 Production of Recombinant 98P4B6 in Prokaryotic Systems

To express recombinant 98P4B6 and 98P4B6 variants in prokaryotic cells,the full or partial length 98P4B6 and 98P4B6 variant cDNA sequences arecloned into any one of a variety of expression vectors known in the art.One or more of the following regions of 98P4B6 variants are expressed:the full length sequence presented in FIGS. 2 and 3, or any 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30 or more contiguous amino acids from 98P4B6, variants, or analogsthereof.

A. In vitro Transcription and Translation Constructs:

pCRII: To generate 98P4B6 sense and anti-sense RNA probes for RNA insitu investigations, pCRII constructs (Invitrogen, Carlsbad Calif.) aregenerated encoding either all or fragments of the 98P4B6 cDNA. The pCRIIvector has Sp6 and T7 promoters flanking the insert to drive thetranscription of 98P4B6 RNA for use as probes in RNA in situhybridization experiments. These probes are used to analyze the cell andtissue expression of 98P4B6 at the RNA level. Transcribed 98P4B6 RNArepresenting the cDNA amino acid coding region of the 98P4B6 gene isused in in vitro translation systems such as the TnT™ CoupledReticulolysate System (Promega, Corp., Madison, Wis.) to synthesize98P4B6 protein.

B. Bacterial Constructs:

PGEX Constructs: To generate recombinant 98P4B6 proteins in bacteriathat are fused to the Glutathione S-transferase (GST) protein, all orparts of the 98P4B6 cDNA protein coding sequence are cloned into thepGEX family of GST-fusion vectors (Amersham Pharmacia Biotech,Piscataway, N.J.). These constructs allow controlled expression ofrecombinant 98P4B6 protein sequences with GST fused at theamino-terminus and a six histidine epitope (6×His) at thecarboxyl-terminus. The GST and 6×His tags permit purification of therecombinant fusion protein from induced bacteria with the appropriateaffinity matrix and allow recognition of the fusion protein withanti-GST and anti-His antibodies. The 6×His tag is generated by adding 6histidine codons to the cloning primer at the 3′ end, e.g., of the openreading frame (ORF). A proteolytic cleavage site, such as thePreScission™ recognition site in pGEX-6P-1, may be employed such that itpermits cleavage of the GST tag from 98P4B6-related protein. Theampicillin resistance gene and pBR322 origin permits selection andmaintenance of the pGEX plasmids in E. coli. A glutathione-S-transferase(GST) fusion protein encompassing amino acids 2-204 of the STEAP-2protein sequence was generated in the pGEX vector. The recombinantGST-STEAP-2 fusion protein was purified from induced bacteria byglutathione-sepaharose affinity chromatography and used as immunogen forgeneration of a polyclonal antibody.

pMAL Constructs: To generate, in bacteria, recombinant 98P4B6 proteinsthat are fused to maltose-binding protein (MBP), all or parts of the98P4B6 cDNA protein coding sequence are fused to the MBP gene by cloninginto the pMAL-c2× and pMAL-p2×vectors (New England Biolabs, Beverly,Mass.). These constructs allow controlled expression of recombinant98P4B6 protein sequences with MBP fused at the amino-terminus and a6×His epitope tag at the carboxyl-terminus. The MBP and 6×His tagspermit purification of the recombinant protein from induced bacteriawith the appropriate affinity matrix and allow recognition of the fusionprotein with anti-MBP and anti-His antibodies. The 6×His epitope tag isgenerated by adding 6 histidine codons to the 3′ cloning primer. AFactor Xa recognition site permits cleavage of the pMAL tag from 98P4B6.The pMAL-c2× and pMAL-p2×vectors are optimized to express therecombinant protein in the cytoplasm or periplasm respectively.Periplasm expression enhances folding of proteins with disulfide bonds.

pET Constructs: To express 98P4B6 in bacterial cells, all or parts ofthe 98P4B6 cDNA protein coding sequence are cloned into the pET familyof vectors (Novagen, Madison, Wis.). These vectors allow tightlycontrolled expression of recombinant 98P4B6 protein in bacteria with andwithout fusion to proteins that enhance solubility, such as NusA andthioredoxin (Trx), and epitope tags, such as 6×His and S-Tag™ that aidpurification and detection of the recombinant protein. For example,constructs are made utilizing pET NusA fusion system 43.1 such thatregions of the 98P4B6 protein are expressed as amino-terminal fusions toNusA.

C. Yeast Constructs:

pESC Constructs: To express 98P4B6 in the yeast species Saccharomycescerevisiae for generation of recombinant protein and functional studies,all or parts of the 98P4B6 cDNA protein coding sequence are cloned intothe pESC family of vectors each of which contain 1 of 4 selectablemarkers, HIS3, TRP1, LEU2, and URA3 (Stratagene, La Jolla, Calif.).These vectors allow controlled expression from the same plasmid of up to2 different genes or cloned sequences containing either Flag™ or Mycepitope tags in the same yeast cell. This system is useful to confirmprotein-protein interactions of 98P4B6. In addition, expression in yeastyields similar post-translational modifications, such as glycosylationsand phosphorylations, that are found when expressed in eukaryotic cells.

pESP Constructs: To express 98P4B6 in the yeast species Saccharomycespombe, all or parts of the 98P4B6 cDNA protein coding sequence arecloned into the pESP family of vectors. These vectors allow controlledhigh level of expression of a 98P4B6 protein sequence that is fused ateither the amino terminus or at the carboxyl terminus to GST which aidspurification of the recombinant protein. A Flag™ epitope tag allowsdetection of the recombinant protein with anti-Flag™ antibody.

Example 8 Production of Recombinant 98P4B6 in Higher Eukaryotic Systems

A. Mammalian Constructs:

To express recombinant 98P4B6 in eukaryotic cells, the full or partiallength 98P4B6 cDNA sequences can be cloned into any one of a variety ofexpression vectors known in the art. One or more of the followingregions of 98P4B6 are expressed in these constructs, amino acids 1 to255, or any 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30 or more contiguous amino acids from98P4B6 v.1 through v.11; amino acids 1 to 1266, or any 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30or more contiguous amino acids from 98P4B6 v.12 and v.13, variants, oranalogs thereof.

The constructs can be transfected into any one of a wide variety ofmammalian cells such as 293T cells. Transfected 293T cell lysates can beprobed with the anti-98P4B6 polyclonal serum, described herein.

pcDNA4/HisMax Constructs: To express 98P4B6 in mammalian cells, a 98P4B6ORF, or portions thereof, of 98P4B6 are cloned into pcDNA4/HisMaxVersion A (Invitrogen, Carlsbad, Calif.). Protein expression is drivenfrom the cytomegalovirus (CMV) promoter and the SP16 translationalenhancer. The recombinant protein has Xpress™ and six histidine (6×His)epitopes fused to the amino-terminus. The pcDNA4/HisMax vector alsocontains the bovine growth hormone (BGH) polyadenylation signal andtranscription termination sequence to enhance mRNA stability along withthe SV40 origin for episomal replication and simple vector rescue incell lines expressing the large T antigen. The Zeocin resistance geneallows for selection of mammalian cells expressing the protein and theampicillin resistance gene and ColE1 origin permits selection andmaintenance of the plasmid in E. coli.

pcDNA3.1/MycHis Constructs: To express 98P4B6 in mammalian cells, a98P4B6 ORF, or portions thereof, of 98P4B6 with a consensus Kozaktranslation initiation site was cloned into pcDNA3.1/MycHis Version A(Invitrogen, Carlsbad, Calif.). Protein expression is driven from thecytomegalovirus (CMV) promoter. The recombinant proteins have the mycepitope and 6×His epitope fused to the carboxyl-terminus. ThepcDNA3.1/MycHis vector also contains the bovine growth hormone (BGH)polyadenylation signal and transcription termination sequence to enhancemRNA stability, along with the SV40 origin for episomal replication andsimple vector rescue in cell lines expressing the large T antigen. TheNeomycin resistance gene can be used, as it allows for selection ofmammalian cells expressing the protein and the ampicillin resistancegene and ColE1 origin permits selection and maintenance of the plasmidin E. coli.

pcDNA3.IIGFP Construct: To express 98P4B6 in mammalian cells and toallow detection of the recombinant proteins using fluorescence, the98P4B6 ORF sequence was codon optimized according to Mirzabekov et al.(1999), and was cloned into pcDNA3.1/GFP vector to generate98P4B6.GFP.pcDNA3.1 construct. Protein expression was driven from thecytomegalovirus (CMV) promoter. The recombinant protein had the GreenFluorescent Protein (GFP) fused to the carboxyl-terminus facilitatingnon-invasive, in vivo detection and cell biology studies. ThepcDNA3.1/GFP vector also contains the bovine growth hormone (BGH)polyadenylation signal and transcription termination sequence to enhancemRNA stability along with the SV40 origin for episomal replication andsimple vector rescue in cell lines expressing the large T antigen. TheNeomycin resistance gene allows for selection of mammalian cells thatexpress the protein, and the ampicillin resistance gene and ColE1 originpermits selection and maintenance of the plasmid in E. coli.

Transfection of 98P4B6.GFP.pcDNA3.1 into 293T cells was performed asshown in FIGS. 17 and 18. Results show strong expression of the fusionprotein by western blot analysis (FIG. 17), flow cytometry (FIG. 18A)and fluorescent microscopy (FIG. 18B).

Additional constructs with an amino-terminal GFP fusion are made inpcDNA3.1/NT-GFP-TOPO spanning the entire length of a 98P4B6 protein.

PAPtag: A 98P4B6 ORF, or portions thereof, is cloned into pAPtag-5(GenHunter Corp. Nashville, Tenn.). This construct generates an alkalinephosphatase fusion at the carboxyl-terminus of a 98P4B6 protein whilefusing the IgGK signal sequence to the amino-terminus. Constructs arealso generated in which alkaline phosphatase with an amino-terminal IgGκsignal sequence is fused to the amino-terminus of a 98P4B6 protein. Theresulting recombinant 98P4B6 proteins are optimized for secretion intothe media of transfected mammalian cells and can be used to identifyproteins such as ligands or receptors that interact with 98P4B6proteins. Protein expression is driven from the CMV promoter and therecombinant proteins also contain myc and 6×His epitopes fused at thecarboxyl-terminus that facilitates detection and purification. TheZeocin resistance gene present in the vector allows for selection ofmammalian cells expressing the recombinant protein and the ampicillinresistance gene permits selection of the plasmid in E coli.

pTa5: A 98P4B6 ORF, or portions thereof, is cloned into pTag-5. Thisvector is similar to pAPtag but without the alkaline phosphatase fusion.This construct generates 98P4B6 protein with an amino-terminal IgGKsignal sequence and myc and 6×His epitope tags at the carboxyl-terminusthat facilitate detection and affinity purification. The resultingrecombinant 98P4B6 protein is optimized for secretion into the media oftransfected mammalian cells, and is used as immunogen or ligand toidentify proteins such as ligands or receptors that interact with the98P4B6 proteins. Protein expression is driven from the CMV promoter. TheZeocin resistance gene present in the vector allows for selection ofmammalian cells expressing the protein, and the ampicillin resistancegene permits selection of the plasmid in E. coli.

PsecFc: A 98P4B6 ORF, or portions thereof, is also cloned into psecFc.The psecFc vector was assembled by cloning the human immunoglobulin G1(IgG) Fc (hinge, CH2, CH3 regions) into pSecTag2 (Invitrogen,California). This construct generates an IgG1 Fc fusion at thecarboxyl-terminus of the 98P4B6 proteins, while fusing the IgGK signalsequence to N-terminus. 98P4B6 fusions utilizing the murine IgG1 Fcregion are also used. The resulting recombinant 98P4B6 proteins areoptimized for secretion into the media of transfected mammalian cells,and can be used as immunogens or to identify proteins such as ligands orreceptors that interact with 98P4B6 protein. Protein expression isdriven from the CMV promoter. The hygromycin resistance gene present inthe vector allows for selection of mammalian cells that express therecombinant protein, and the ampicillin resistance gene permitsselection of the plasmid in E. coli.

DSRα Constructs: To generate mammalian cell lines that express 98P4B6constitutively, 98P4B6 ORF, or portions thereof, of 98P4B6 were clonedinto pSRα constructs. Amphotropic and ecotropic retroviruses weregenerated by transfection of pSRα constructs into the 293T-1 OA1packaging line or co-transfection of pSRα and a helper plasmid(containing deleted packaging sequences) into the 293 cells,respectively. The retrovirus is used to infect a variety of mammaliancell lines, resulting in the integration of the cloned gene, 98P4B6,into the host cell-lines. Protein expression is driven from a longterminal repeat (LTR). The Neomycin resistance gene present in thevector allows for selection of mammalian cells that express the protein,and the ampicillin resistance gene and ColE1 origin permit selection andmaintenance of the plasmid in E. coli. The retroviral vectors canthereafter be used for infection and generation of various cell linesusing, for example, PC3, NIH 3T3, TsuPr1, 293 or rat-1 cells.

Additional pSRα constructs are made that fuse an epitope tag such as theFLAG™ tag to the carboxyl-terminus of 98P4B6 sequences to allowdetection using anti-Flag antibodies. For example, the FLAG™ sequence 5′gat tac aag gat gac gac gat aag 3′ (SEQ ID NO: 113) is added to cloningprimer at the 3′ end of the ORF. Additional pSRα constructs are made toproduce both amino-terminal and carboxyl-terminal GFP and myc/6×Hisfusion proteins of the full-length 98P4B6 proteins.

Additional Viral Vectors: Additional constructs are made forviral-mediated delivery and expression of 98P4B6. High virus titerleading to high level expression of 98P4B6 is achieved in viral deliverysystems such as adenoviral vectors and herpes amplicon vectors. A 98P4B6coding sequences or fragments thereof are amplified by PCR and subclonedinto the AdEasy shuttle vector (Stratagene). Recombination and viruspackaging are performed according to the manufacturer's instructions togenerate adenoviral vectors. Alternatively, 98P4B6 coding sequences orfragments thereof are cloned into the HSV-1 vector (Imgenex) to generateherpes viral vectors. The viral vectors are thereafter used forinfection of various cell lines such as PC3, NIH 3T3, 293 or rat-1cells.

Regulated Expression Systems: To control expression of 98P4B6 inmammalian cells, coding sequences of 98P4B6, or portions thereof, arecloned into regulated mammalian expression systems such as the T-RexSystem (Invitrogen), the GeneSwitch System (Invitrogen) and thetightly-regulated Ecdysone System (Sratagene). These systems allow thestudy of the temporal and concentration dependent effects of recombinant98P4B6. These vectors are thereafter used to control expression of98P4B6 in various cell lines such as PC3, NIH 3T3, 293 or rat-1 cells.

B. Baculovirus Expression Systems

To generate recombinant 98P4B6 proteins in a baculovirus expressionsystem, 98P4B6 ORF, or portions thereof, are cloned into the baculovirustransfer vector pBlueBac 4.5 (Invitrogen), which provides a His-tag atthe N-terminus. Specifically, pBlueBac-98P4B6 is co-transfected withhelper plasmid pBac-N-Blue (Invitrogen) into SF9 (Spodoptera frugiperda)insect cells to generate recombinant baculovirus (see Invitrogeninstruction manual for details). Baculovirus is then collected from cellsupernatant and purified by plaque assay.

Recombinant 98P4B6 protein is then generated by infection of HighFiveinsect cells (Invitrogen) with purified baculovirus. Recombinant 98P4B6protein can be detected using anti-98P4B6 or anti-His-tag antibody.98P4B6 protein can be purified and used in various cell-based assays oras immunogen to generate polyclonal and monoclonal antibodies specificfor 98P4B6.

Example 9 Antigenicity Profiles and Secondary Structure

FIG. 5(A-E), FIG. 6(A-E), FIG. 7(A-E), FIG. 8(A-E), and FIG. 9(A-E)depict graphically five amino acid profiles of 98P4B6 variants 1, 2,5-7, each assessment available by accessing the ProtScale websitelocated on the ExPasy molecular biology server.

These profiles: FIG. 5, Hydrophilicity, (Hopp T. P., Woods K. R., 1981.Proc. Natl. Acad. Sci. U.S.A. 78:3824-3828); FIG. 6, Hydropathicity,(Kyte J., Doolittle R. F., 1982. J. Mol. Biol. 157:105-132); FIG. 7,Percentage Accessible Residues (Janin J., 1979 Nature 277:491-492); FIG.8, Average Flexibility, (Bhaskaran R., and Ponnuswamy P. K., 1988. Int.J. Pept. Protein Res. 32:242-255); FIG. 9, Beta-turn (Deleage, G., RouxB. 1987 Protein Engineering 1:289-294); and optionally others availablein the art, such as on the ProtScale website, were used to identifyantigenic regions of each of the 98P4B6 variant proteins. Each of theabove amino acid profiles of 98P4B6 variants were generated using thefollowing ProtScale parameters for analysis: 1) A window size of 9; 2)100% weight of the window edges compared to the window center; and, 3)amino acid profile values normalized to lie between 0 and 1.

Hydrophilicity (FIG. 5), Hydropathicity (FIG. 6) and PercentageAccessible Residues (FIG. 7) profiles were used to determine stretchesof hydrophilic amino acids (i.e., values greater than 0.5 on theHydrophilicity and Percentage Accessible Residues profile, and valuesless than 0.5 on the Hydropathicity profile). Such regions are likely tobe exposed to the aqueous environment, be present on the surface of theprotein, and thus available for immune recognition, such as byantibodies.

Average Flexibility (FIG. 8) and Beta-turn (FIG. 9) profiles determinestretches of amino acids (i.e., values greater than 0.5 on the Beta-turnprofile and the Average Flexibility profile) that are not constrained insecondary structures such as beta sheets and alpha helices. Such regionsare also more likely to be exposed on the protein and thus accessible toimmune recognition, such as by antibodies.

Antigenic sequences of the 98P4B6 variant proteins indicated, e.g., bythe profiles set forth in FIG. 5(A-E), FIG. 6(A-E), FIG. 7(A-E), FIG.8(A-E), and/or FIG. 9(A-E) are used to prepare immunogens, eitherpeptides or nucleic acids that encode them, to generate therapeutic anddiagnostic anti-98P4B6 antibodies. The immunogen can be any 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30,35, 40, 45, 50 or more than 50 contiguous amino acids, or thecorresponding nucleic acids that encode them, from the 98P4B6 proteinvariants 1, 2, 5-7 listed in FIGS. 2 and 3. In particular, peptideimmunogens of the invention can comprise, a peptide region of at least 5amino acids of FIGS. 2 and 3 in any whole number increment that includesan amino acid position having a value greater than 0.5 in theHydrophilicity profiles of FIG. 5; a peptide region of at least 5 aminoacids of FIGS. 2 and 3 in any whole number increment that includes anamino acid position having a value less than 0.5 in the Hydropathicityprofile of FIGS. 6; a peptide region of at least 5 amino acids of FIGS.2 and 3 in any whole number increment that includes an amino acidposition having a value greater than 0.5 in the Percent AccessibleResidues profiles of FIG. 7; a peptide region of at least 5 amino acidsof FIGS. 2 and 3 in any whole number increment that includes an aminoacid position having a value greater than 0.5 in the Average Flexibilityprofiles on FIG. 8 ; and, a peptide region of at least 5 amino acids ofFIGS. 2 and 3 in any whole number increment that includes an amino acidposition having a value greater than 0.5 in the Beta-turn profile ofFIG. 9. Peptide immunogens of the invention can also comprise nucleicacids that encode any of the forgoing.

All immunogens of the invention, peptide or nucleic acid, can beembodied in human unit dose form, or comprised by a composition thatincludes a pharmaceutical excipient compatible with human physiology.

The secondary structure of 98P4B6 protein variants 1, 2, 5-7, namely thepredicted presence and location of alpha helices, extended strands, andrandom coils, is predicted from the primary amino acid sequence usingthe HNN—Hierarchical Neural Network method, accessed from the ExPasymolecular biology server. The analysis indicates that 98P4B6 variant 1is composed of 54.41% alpha helix, 12.33% extended strand, and 33.26%random coil (FIG. 13A). Variant 2 is composed of 17.78% alpha helix,6.67% extended strand, and 75.56% random coil (FIG. 13B). Variant 5 iscomposed of 51.55% alpha helix, 13.13% extended strand, and 35.32%random coil (FIG. 13C). Variant 6 is composed of 54.49% alpha helix,11.84% extended strand, and 33.67% random coil (FIG. 13D). Variant 7 iscomposed of 48.26% alpha helix, 15.28% extended strand, and 36.46%random coil (FIG. 13E).

Analysis for the potential presence of transmembrane domains in the98P4B6 variant proteins was carried out using a variety of transmembraneprediction algorithms accessed from the ExPasy molecular biology server.Shown graphically in FIG. 13F and 13G are the results of analysis ofvariant 1 depicting the presence and location of 6 transmembrane domainsusing the TMpred program (FIG. 13F) and 5 transmembrane domains usingthe TMHMM program (FIG. 13G). Shown graphically in FIG. 13H and 13I arethe results of analysis of variant 2 depicting the presence and locationof 1 transmembrane domains using the TMpred program (FIG. 13H) and notransmembrane domains using the TMHMM program (FIG. 13I). Showngraphically in FIG. 13J and 13K are the results of analysis of variant 5depicting the presence and location of 6 transmembrane domains using theTMpred program (FIG. 13J) and 4 transmembrane domains using the TMHMMprogram (FIG. 13K). Shown graphically in FIG. 13L and 13M are theresults of analysis of variant 6 depicting the presence and location of6 transmembrane domains using the TMpred program (FIG. 13L) and 6transmembrane domains using the TMHMM program (FIG. 13M). Showngraphically in FIG. 13N and 130 are the results of analysis of variant 7depicting the presence and location of 6 transmembrane domains using theTMpred program (FIG. 13N) and 4 transmembrane domains using the TMHMMprogram (FIG. 13O). The results of each program, namely the amino acidsencoding the transmembrane domains are summarized in Table VI.

Example 10 Generation of 98P4B6 Polyclonal Antibodies

Polyclonal antibodies can be raised in a mammal, for example, by one ormore injections of an immunizing agent and, if desired, an adjuvant.Typically, the immunizing agent and/or adjuvant will be injected in themammal by multiple subcutaneous or intraperitoneal injections. Inaddition to immunizing with a full length 98P4B6 protein variant,computer algorithms are employed in design of immunogens that, based onamino acid sequence analysis contain characteristics of being antigenicand available for recognition by the immune system of the immunized host(see Example 9 entitled “Antigenicity Profiles and SecondaryStructure”). Such regions would be predicted to be hydrophilic,flexible, in beta-turn conformations, and be exposed on the surface ofthe protein (see, e.g., FIG. 5(A-E), FIG. 6(A & B), FIG. 7(A-E), FIG.8(A -E), or FIG. 9(A-E) for amino acid profiles that indicate suchregions of 98P4B6 protein variants).

For example, recombinant bacterial fusion proteins or peptidescontaining hydrophilic, flexible, beta-turn regions of 98P4B6 proteinvariants are used as antigens to generate polyclonal antibodies in NewZealand White rabbits or monoclonal antibodies as described in Example11. For example, in 98P4B6 variant 1, such regions include, but are notlimited to, amino acids 153-165, amino acids 240-260, and amino acids345-358. In sequence specific for variant 2, such regions include, butare not limited to, amino acids 26-38. In sequence specific for variant5, such regions include, but are not limited to, amino acids 400-410. Insequence specific for variant 6, such regions include, but are notlimited to, amino acids 455-490. In sequence specific for variant 7,such regions include, but are not limited to, amino acids 451-465 andamino acids 472-498. It is useful to conjugate the immunizing agent to aprotein known to be immunogenic in the mammal being immunized. Examplesof such immunogenic proteins include, but are not limited to, keyholelimpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, andsoybean trypsin inhibitor. In one embodiment, a peptide encoding aminoacids 153-165 of 98P4B6 variant 1 was conjugated to KLH and used toimmunize a rabbit. Alternatively the immunizing agent may include all orportions of the 98P4B6 variant proteins, analogs or fusion proteinsthereof. For example, the 98P4B6 variant 1 amino acid sequence can befused using recombinant DNA techniques to any one of a variety of fusionprotein partners that are well known in the art, such asglutathione-S-transferase (GST) and HIS tagged fusion proteins. Inanother embodiment, amino acids 2-204 of 98P4B6 variant 1 was fused toGST using recombinant techniques and the pGEX expression vector,expressed, purified and used to immunize a rabbit. Such fusion proteinsare purified from induced bacteria using the appropriate affinitymatrix.

Other recombinant bacterial fusion proteins that may be employed includemaltose binding protein, LacZ, thioredoxin, NusA, or an immunoglobulinconstant region (see the section entitled “Production of 98P4B6 inProkaryotic Systems” and Current Protocols In Molecular Biology, Volume2, Unit 16, Frederick M. Ausubul et al. eds., 1995; Linsley, P. S.,Brady, W., Umes, M., Grosmaire, L., Damle, N., and Ledbetter, L. (1991)J. Exp. Med. 174, 561-566).

In addition to bacterial derived fusion proteins, mammalian expressedprotein antigens are also used. These antigens are expressed frommammalian expression vectors such as the Tag5 and Fc-fusion vectors (seethe section entitled “Production of Recombinant 98P4B6 in EukaryoticSystems”), and retain post-translational modifications such asglycosylations found in native protein. In one embodiment, amino acids324-359 of variant 1, encoding an extracellular loop betweentransmembrane domains, is cloned into the Tag5 mammalian secretionvector. The recombinant protein is purified by metal chelatechromatography from tissue culture supernatants of 293T cells stablyexpressing the recombinant vector. The purified Tag5 98P4B6 protein isthen used as immunogen.

During the immunization protocol, it is useful to mix or emulsify theantigen in adjuvants that enhance the immune response of the hostanimal. Examples of adjuvants include, but are not limited to, completeFreund's adjuvant (CFA) and MPL-TDM adjuvant (monophosphoryl Lipid A,synthetic trehalose dicorynomycolate).

In a typical protocol, rabbits are initially immunized subcutaneouslywith up to 200 μg, typically 100-200 μg, of fusion protein or peptideconjugated to KLH mixed in complete Freund's adjuvant (CFA). Rabbits arethen injected subcutaneously every two weeks with up to 200 μg,typically 100-200 μg, of the immunogen in incomplete Freund's adjuvant(IFA). Test bleeds are taken approximately 7-10 days following eachimmunization and used to monitor the titer of the antiserum by ELISA.

To test reactivity and specificity of immune serum, such as the rabbitserum derived from immunization with the Tag5-98P4B6 variant 1 protein,the full-length 98P4B6 variant 1 cDNA is cloned into pCDNA 3.1 myc-hisexpression vector (Invitrogen, see the Example entitled “Production ofRecombinant 98P4B6 in Eukaryotic Systems”). After transfection of theconstructs into 293T cells, cell lysates are probed with the anti-98P4B6serum and with anti-His antibody (Santa Cruz Biotechnologies, SantaCruz, Calif.) to determine specific reactivity to denatured 98P4B6protein using the Western blot technique. Detection of 98P4B6 variant 1protein expressed in 293T with polyclonal antibodies raised to aGST-fusion protein and peptide is shown in FIGS. 17B and 17C,respectively. In addition, the immune serum is tested by fluorescencemicroscopy, flow cytometry and immunoprecipitation against 293T andother recombinant 98P4B6-expressing cells to determine specificrecognition of native protein. Western blot, immunoprecipitation,fluorescent microscopy, and flow cytometric techniques using cells thatendogenously express 98P4B6 are also carried out to test reactivity andspecificity.

Anti-serum from rabbits immunized with 98P4B6 variant fusion proteins,such as GST and MBP fusion proteins, are purified by depletion ofantibodies reactive to the fusion partner sequence by passage over anaffinity column containing the fusion partner either alone or in thecontext of an irrelevant fusion protein. For example, antiserum derivedfrom a GST-98P4B6 variant 1 fusion protein was first purified by passageover a column of GST protein covalently coupled to AffiGel matrix(BioRad, Hercules, Calif.). The antiserum is then affinity purified bypassage over a column composed of a MBP-98P4B6 fusion protein covalentlycoupled to Affigel matrix. The serum is then further purified by proteinG affinity chromatography to isolate the IgG fraction. Sera from otherHis-tagged antigens and peptide immunized rabbits as well as fusionpartner depleted sera are affinity purified by passage over a columnmatrix composed of the original protein immunogen or free peptide, suchas the anti-peptide polyclonal antibody used in FIG. 17C.

Example 11 Generation of 98P4B6 Monoclonal Antibodies (mAbs)

In one embodiment, therapeutic mAbs to 98P4B6 variants comprise thosethat react with epitopes specific for each variant protein or specificto sequences in common between the variants that would disrupt ormodulate the biological function of the 98P4B6 variants, for examplethose that would disrupt the interaction with ligands and bindingpartners. Immunogens for generation of such mAbs include those designedto encode or contain the entire 98P4B6 protein variant sequence, regionsof the 98P4B6 protein variants predicted to be antigenic from computeranalysis of the amino acid sequence (see, e.g., FIG. 5(A-E), FIG.6(A-E), FIG. 7(A-E), FIG. 8(A-E), or FIG. 9(A-E), and Example 9 entitled“Antigenicity Profiles and Secondary Structure”). Immunogens includepeptides, recombinant bacterial proteins, and mammalian expressed Tag 5proteins and human and murine IgG FC fusion proteins. In addition, cellsengineered to express high levels of a respective 98P4B6 variant, suchas 293T-98P4B6 variant 1 or 300.19-98P4B6 variant 1murine Pre-B cells,are used to immunize mice.

To generate mAbs to a 98P4B6 variant, mice are first immunizedintraperitoneally (IP) with, typically, 10-50 μg of protein immunogen or10⁷ 98P4B6-expressing cells mixed in complete Freund's adjuvant. Miceare then subsequently immunized IP every 2-4 weeks with, typically,10-50 μg of protein immunogen or 10⁷ cells mixed in incomplete Freund'sadjuvant. Alternatively, MPL-TDM adjuvant is used in immunizations. Inaddition to the above protein and cell-based immunization strategies, aDNA-based immunization protocol is employed in which a mammalianexpression vector encoding a 98P4B6 variant sequence is used to immunizemice by direct injection of the plasmid DNA. For example, amino acids324-359 is cloned into the Tag5 mammalian secretion vector and therecombinant vector is used as immunogen. In another example the sameamino acids are cloned into an Fc-fusion secretion vector in which the98P4B6 variant 1 sequence is fused at the amino-terminus to an IgKleader sequence and at the carboxyl-terminus to the coding sequence ofthe human or murine IgG Fc region. This recombinant vector is then usedas immunogen. The plasmid immunization protocols are used in combinationwith purified proteins expressed from the same vector and with cellsexpressing the respective 98P4B6 variant.

During the immunization protocol, test bleeds are taken 7-10 daysfollowing an injection to monitor titer and specificity of the immuneresponse. Once appropriate reactivity and specificity is obtained asdetermined by ELISA, Western blotting, immunoprecipitation, fluorescencemicroscopy, and flow cytometric analyses, fusion and hybridomageneration is then carried out with established procedures well known inthe art (see, e.g., Harlow and Lane, 1988).

In one embodiment for generating 98P4B6 monoclonal antibodies, aTag5-98P4B6 variant 1 antigen encoding amino acids 324-359, is expressedand purified from stably transfected 293T cells. Balb C mice areinitially immunized intraperitoneally with 25 μg of the Tag5-98P4B6variant 1 protein mixed in complete Freund's adjuvant. Mice aresubsequently immunized every two weeks with 25 μg of the antigen mixedin incomplete Freund's adjuvant for a total of three immunizations.ELISA using the Tag5 antigen determines the titer of serum fromimmunized mice. Reactivity and specificity of serum to full length98P4B6 variant 1 protein is monitored by Western blotting,immunoprecipitation and flow cytometry using 293T cells transfected withan expression vector encoding the 98P4B6 variant 1 cDNA (see e.g., theExample entitled “Production of Recombinant 98P4B6 in EukaryoticSystems” and FIG. 20). Other recombinant 98P4B6 variant 1-expressingcells or cells endogenously expressing 98P4B6 variant 1 are also used.Mice showing the strongest reactivity are rested and given a finalinjection of Tag5 antigen in PBS and then sacrificed four days later.The spleens of the sacrificed mice are harvested and fused to SPO/2myeloma cells using standard procedures (Harlow and Lane, 1988).Supernatants from HAT selected growth wells are screened by ELISA,Western blot, immunoprecipitation, fluorescent microscopy, and flowcytometry to identify 98P4B6 specific antibody-producing clones.

To generate monoclonal antibodies that are specific for each 98P4B6variant protein, immunogens are designed to encode sequences unique foreach variant. In one embodiment, a Tag5 antigen encoding the fullsequence of 98P4B6 variant 2 (M 1-45) is produced, purified and used asimmunogen to derive monoclonal antibodies specific to 98P4B6 variant 2.In another embodiment, an antigenic peptide composed of amino acids400-410 of 98P4B6 variant 5 is coupled to KLH and used as immunogen. Inanother embodiment, a GST fusion protein encoding amino acids 455-490 of98P4B6 of variant 6 is used as immunogen to derive variant 6 specificmonoclonal antibodies. In another embodiment, a peptide composed ofamino acids 472-498 of variant 7 is coupled to KLH and used as immunogento generate variant 7 specific monoclonal antibodies. Hybridomasupernatants are then screened on the respective antigen and thenfurther screened on cells expressing the specific variant andcross-screened on cells expressing the other variants to derivevariant-specific monoclonal antibodies.

The binding affinity of a 98P4B6 variant monoclonal antibody isdetermined using standard technologies. Affinity measurements quantifythe strength of antibody to epitope binding and are used to help definewhich 98P4B6 variant monoclonal antibodies preferred for diagnostic ortherapeutic use, as appreciated by one of skill in the art. The BIAcoresystem (Uppsala, Sweden) is a preferred method for determining bindingaffinity. The BIAcore system uses surface plasmon resonance (SPR,Welford K. 1991, Opt. Quant. Elect. 23:1; Morton and Myszka, 1998,Methods in Enzymology 295: 268) to monitor biomolecular interactions inreal time. BIAcore analysis conveniently generates association rateconstants, dissociation rate constants, equilibrium dissociationconstants, and affinity constants.

Example 12 HLA Class I and Class II Binding Assays

HLA class I and class II binding assays using purified HLA molecules areperformed in accordance with disclosed protocols (e.g., PCT publicationsWO 94/20127 and WO 94/03205; Sidney et al., Current Protocols inImmunology 18.3.1 (1998); Sidney, et al., J. Immunol. 154:247 (1995);Sette, et al., Mol. Immunol. 31:813 (1994)). Briefly, purified MHCmolecules (5 to 500 nM) are incubated with various unlabeled peptideinhibitors and 1-10 nM¹²⁵I-radiolabeled probe peptides as described.Following incubation, MHC-peptide complexes are separated from freepeptide by gel filtration and the fraction of peptide bound isdetermined. Typically, in preliminary experiments, each MHC preparationis titered in the presence of fixed amounts of radiolabeled peptides todetermine the concentration of HLA molecules necessary to bind 10-20% ofthe total radioactivity. All subsequent inhibition and direct bindingassays are performed using these HLA concentrations.

Since under these conditions [label]<[HLA] and IC₅₀≧[HLA], the measuredIC₅₀ values are reasonable approximations of the true K_(D) values.Peptide inhibitors are typically tested at concentrations ranging from120 μg/ml to 1.2 ng/ml, and are tested in two to four completelyindependent experiments. To allow comparison of the data obtained indifferent experiments, a relative binding figure is calculated for eachpeptide by dividing the IC₅₀ of a positive control for inhibition by theIC₅₀ for each tested peptide (typically unlabeled versions of theradiolabeled probe peptide). For database purposes, and inter-experimentcomparisons, relative binding values are compiled. These values cansubsequently be converted back into IC₅₀ nM values by dividing the IC₅₀nM of the positive controls for inhibition by the relative binding ofthe peptide of interest. This method of data compilation is accurate andconsistent for comparing peptides that have been tested on differentdays, or with different lots of purified MHC.

Binding assays as outlined above may be used to analyze HLA supermotifand/or HLA motif-bearing peptides (see Table IV).

Example 13 Identification of HLA Supermotif- and Motif-Bearing CTLCandidate Epitopes

HLA vaccine compositions of the invention can include multiple epitopes.The multiple epitopes can comprise multiple HLA supermotifs or motifs toachieve broad population coverage. This example illustrates theidentification and confirmation of supermotif- and motif-bearingepitopes for the inclusion in such a vaccine composition. Calculation ofpopulation coverage is performed using the strategy described below.

Computer Searches and Algorithms for Identification of Supermotif and/orMotif-Bearing Epitopes

The searches performed to identify the motif-bearing peptide sequencesin the Example entitled “Antigenicity Profiles” and Tables VIII-XXI andXXII-XLIX employ the protein sequence data from the gene product of98P4B6 set forth in FIGS. 2 and 3, the specific search peptides used togenerate the tables are listed in Table VII.

Computer searches for epitopes bearing HLA Class I or Class IIsupermotifs or motifs are performed as follows. All translated 98P4B6protein sequences are analyzed using a text string search softwareprogram to identify potential peptide sequences containing appropriateHLA binding motifs; such programs are readily produced in accordancewith information in the art in view of known motif/supermotifdisclosures. Furthermore, such calculations can be made mentally.

Identified A2-, A3-, and DR-supermotif sequences are scored usingpolynomial algorithms to predict their capacity to bind to specificHLA-Class I or Class II molecules. These polynomial algorithms accountfor the impact of different amino acids at different positions, and areessentially based on the premise that the overall affinity (or AG) ofpeptide-HLA molecule interactions can be approximated as a linearpolynomial function of the type:“ΔG”=a _(1i) ×a _(2i) ×a _(3i) . . . ×a _(ni)where a_(ji) is a coefficient which represents the effect of thepresence of a given amino acid (j) at a given position (i) along thesequence of a peptide of n amino acids. The crucial assumption of thismethod is that the effects at each position are essentially independentof each other (i.e., independent binding of individual side-chains).When residue j occurs at position i in the peptide, it is assumed tocontribute a constant amount ji to the free energy of binding of thepeptide irrespective of the sequence of the rest of the peptide.

The method of derivation of specific algorithm coefficients has beendescribed in Gulukota et al., J. Mol. Biol. 267:1258-126, 1997; (seealso Sidney et al., Human Immunol. 45:79-93, 1996; and Southwood et al.,J. Immunol. 160:3363-3373, 1998). Briefly, for all i positions, anchorand non-anchor alike, the geometric mean of the average relative binding(ARB) of all peptides carrying j is calculated relative to the remainderof the group, and used as the estimate of ji. For Class II peptides, ifmultiple alignments are possible, only the highest scoring alignment isutilized, following an iterative procedure. To calculate an algorithmscore of a given peptide in a test set, the ARB values corresponding tothe sequence of the peptide are multiplied. If this product exceeds achosen threshold, the peptide is predicted to bind. Appropriatethresholds are chosen as a function of the degree of stringency ofprediction desired.

Selection of HLA-A2 Supertype Cross-Reactive Peptides

Protein sequences from 98P4B6 are scanned utilizing motif identificationsoftware, to identify 8-, 9- 10- and 11-mer sequences containing theHLA-A2-supermotif main anchor specificity. Typically, these sequencesare then scored using the protocol described above and the peptidescorresponding to the positive-scoring sequences are synthesized andtested for their capacity to bind purified HLA-A*0201 molecules in vitro(HLA-A*0201 is considered a prototype A2 supertype molecule).

These peptides are then tested for the capacity to bind to additionalA2-supertype molecules (A*0202, A*0203, A*0206, and A*6802). Peptidesthat bind to at least three of the five A2-supertype alleles tested aretypically deemed A2-supertype cross-reactive binders. Preferred peptidesbind at an affinity equal to or less than 500 nM to three or more HLA-A2supertype molecules.

Selection of HLA-A3 Supermotif-Bearing Epitopes

The 98P4B6 protein sequence(s) scanned above is also examined for thepresence of peptides with the HLA-A3-supermotif primary anchors.Peptides corresponding to the HLA A3 supermotif-bearing sequences arethen synthesized and tested for binding to HLA-A*0301 and HLA-A*1101molecules, the molecules encoded by the two most prevalent A3-supertypealleles. The peptides that bind at least one of the two alleles withbinding affinities of ≦500 nM, often ≦200 nM, are then tested forbinding cross-reactivity to the other common A3-supertype alleles (e.g.,A*3101, A*3301, and A*6801) to identify those that can bind at leastthree of the five HLA-A3-supertype molecules tested.

Selection of HLA-B7 Supermotif Bearing Epitopes

The 98P4B6 protein(s) scanned above is also analyzed for the presence of8-, 9- 10-, or 11-mer peptides with the HLA-B7-supermotif. Correspondingpeptides are synthesized and tested for binding to HLA-B*0702, themolecule encoded by the most common B7-supertype allele (i.e., theprototype B7 supertype allele). Peptides binding B*0702 with IC₅₀ of≦500 nM are identified using standard methods. These peptides are thentested for binding to other common B7-supertype molecules (e.g., B*3501,B*5101, B*5301, and B*5401). Peptides capable of binding to three ormore of the five B7-supertype alleles tested are thereby identified.

Selection of A1 and A24 Motif-Bearing Epitopes

To further increase population coverage, HLA-A1 and -A24 epitopes canalso be incorporated into vaccine compositions. An analysis of the98P4B6 protein can also be performed to identify HLA-A1- andA24-motif-containing sequences.

High affinity and/or cross-reactive binding epitopes that bear othermotif and/or supermotifs are identified using analogous methodology.

Example 14 Confirmation of Immunogenicity

Cross-reactive candidate CTL A2-supermotif-bearing peptides that areidentified as described herein are selected to confirm in vitroimmunogenicity. Confirmation is performed using the followingmethodology:

Target Cell Lines for Cellular Screening:

The 0.221A2.1 cell line, produced by transferring the HLA-A2.1 gene intothe HLA-A, -B, -C null mutant human B-lymphoblastoid cell line 721.221,is used as the peptide-loaded target to measure activity ofHLA-A2.1-restricted CTL. This cell line is grown in RPMI-1640 mediumsupplemented with antibiotics, sodium pyruvate, nonessential amino acidsand 10% (v/v) heat inactivated FCS. Cells that express an antigen ofinterest, or transfectants comprising the gene encoding the antigen ofinterest, can be used as target cells to confirm the ability ofpeptide-specific CTLs to recognize endogenous antigen.

Primary CTL Induction Cultures:

Generation of Dendritic Cells (DC): PBMCs are thawed in RPMI with 30μg/ml DNAse, washed twice and resuspended in complete medium (RPMI-1640plus 5% AB human serum, non-essential amino acids, sodium pyruvate,L-glutamine and penicillin/streptomycin). The monocytes are purified byplating 10×10⁶ PBMC/well in a 6-well plate. After 2 hours at 37° C., thenon-adherent cells are removed by gently shaking the plates andaspirating the supernatants. The wells are washed a total of three timeswith 3 ml RPMI to remove most of the non-adherent and loosely adherentcells. Three ml of complete medium containing 50 ng/ml of GM-CSF and1,000 U/ml of IL-4 are then added to each well. TNFα is added to the DCson day 6 at 75 ng/ml and the cells are used for CTL induction cultureson day 7.

Induction of CTL with DC and Peptide: CD8+ T-cells are isolated bypositive selection with Dynal immunomagnetic beads (Dynabeads® M-450)and the detacha-bead® reagent. Typically about 200-250×10⁶ PBMC areprocessed to obtain 24×106 CD8+ T-cells (enough for a 48-well plateculture). Briefly, the PBMCs are thawed in RPMI with 30 μg/ml DNAse,washed once with PBS containing 1% human AB serum and resuspended inPBS/1% AB serum at a concentration of 20×10⁶ cells/ml. The magneticbeads are washed 3 times with PBS/AB serum, added to the cells (140 μlbeads/20×10⁶ cells) and incubated for 1 hour at 4° C. with continuousmixing. The beads and cells are washed 4× with PBS/AB serum to removethe nonadherent cells and resuspended at 100×10⁶ cells/ml (based on theoriginal cell number) in PBS/AB serum containing 100 μl/ml detacha-bead®reagent and 30 μg/ml DNAse. The mixture is incubated for 1 hour at roomtemperature with continuous mixing. The beads are washed again withPBS/AB/DNAse to collect the CD8+ T-cells. The DC are collected andcentrifuged at 1300 rpm for 5-7 minutes, washed once with PBS with 1%BSA, counted and pulsed with 40μg/ml of peptide at a cell concentrationof 1-2×10⁶/ml in the presence of 3 μg/ml β₂-microglobulin for 4 hours at20° C. The DC are then irradiated (4,200 rads), washed 1 time withmedium and counted again.

Setting up induction cultures: 0.25 ml cytokine-generated DC (at 1×10⁵cells/ml) are co-cultured with 0.25 ml of CD8+ T-cells (at 2×10⁶cell/ml) in each well of a 48-well plate in the presence of 10 ng/ml ofIL-7. Recombinant human IL-10 is added the next day at a finalconcentration of 10 ng/ml and rhuman IL-2 is added 48 hours later at 10IU/ml.

Restimulation of the induction cultures with peptide-pulsed adherentcells: Seven and fourteen days after the primary induction, the cellsare restimulated with peptide-pulsed adherent cells. The PBMCs arethawed and washed twice with RPMI and DNAse. The cells are resuspendedat 5×10⁶ cells/ml and irradiated at ˜4200 rads. The PBMCs are plated at2×10⁶ in 0.5 ml complete medium per well and incubated for 2 hours at37° C. The plates are washed twice with RPMI by tapping the plate gentlyto remove the nonadherent cells and the adherent cells pulsed with 10g/ml of peptide in the presence of 3 μg/ml 92 microglobulin in 0.25mlRPMI/5%AB per well for 2 hours at 37° C. Peptide solution from each wellis aspirated and the wells are washed once with RPMI. Most of the mediais aspirated from the induction cultures (CD8+ cells) and brought to 0.5ml with fresh media. The cells are then transferred to the wellscontaining the peptide-pulsed adherent cells. Twenty four hours laterrecombinant human IL-10 is added at a final concentration of 10 ng/mland recombinant human IL2 is added the next day and again 2-3 days laterat 50 IU/ml (Tsai et al., Critical Reviews in Immunology 18(1-2):65-75,1998). Seven days later, the cultures are assayed for CTL activity in a⁵¹Cr release assay. In some experiments the cultures are assayed forpeptide-specific recognition in the in situ IFNγ ELISA at the time ofthe second restimulation followed by assay of endogenous recognition 7days later. After expansion, activity is measured in both assays for aside-by-side comparison.

Measurement of CTL Lytic Activity by ⁵¹Cr Release.

Seven days after the second restimulation, cytotoxicity is determined ina standard (5 hr) ⁵¹Cr release assay by assaying individual wells at asingle E:T. Peptide-pulsed targets are prepared by incubating the cellswith 10 μg/ml peptide overnight at 37° C.

Adherent target cells are removed from culture flasks with trypsin-EDTA.Target cells are labeled with 200 μCl of ⁵¹Cr sodium chromate (DuPont,Wilmington, Del.) for 1 hour at 37° C. Labeled target cells areresuspended at 10⁶ per ml and diluted 1:10 with K562 cells at aconcentration of 3.3×10⁶/ml (an NK-sensitive erythroblastoma cell lineused to reduce non-specific lysis). Target cells (100 μl) and effectors(100μl) are plated in 96 well round-bottom plates and incubated for 5hours at 37° C. At that time, 100 μl of supernatant are collected fromeach well and percent lysis is determined according to the formula:[(cpm of the test sample−cpm of the spontaneous ⁵¹Cr releasesample)/(cpm of the maximal ⁵¹Cr release sample−cpm of the spontaneous⁵¹Cr release sample)]×100.

Maximum and spontaneous release are determined by incubating the labeledtargets with 1% Triton X-100 and media alone, respectively. A positiveculture is defined as one in which the specific lysis(sample-background) is 10% or higher in the case of individual wells andis 15% or more at the two highest E:T ratios when expanded cultures areassayed.

In situ Measurement of Human IFNγ Production as an Indicator ofPeptide-specific and Endogenous Recognition

Immulon 2 plates are coated with mouse anti-human IFNγ monoclonalantibody (4 μg/ml 0.1M NaHCO₃, pH8.2) overnight at 4° C. The plates arewashed with Ca²⁺, Mg²⁺-free PBS/0.05% Tween 20 and blocked with PBS/10%FCS for two hours, after which the CTLs (100 μl/well) and targets (100μl/well) are added to each well, leaving empty wells for the standardsand blanks (which received media only). The target cells, eitherpeptide-pulsed or endogenous targets, are used at a concentration of1×10⁶ cells/ml. The plates are incubated for 48 hours at 37° C. with 5%CO₂.

Recombinant human IFN-gamma is added to the standard wells starting at400 pg or 1200 pg/100 microliter/well and the plate incubated for twohours at 37° C. The plates are washed and 100 μl of biotinylated mouseanti-human IFN-gamma monoclonal antibody (2 microgram/ml in PBS/3%FCS/0.05% Tween 20) are added and incubated for 2 hours at roomtemperature. After washing again, 100 microliter HRP-streptavidin(1:4000) are added and the plates incubated for one hour at roomtemperature. The plates are then washed 6× with wash buffer, 100microliter/well developing solution (TMB 1:1) are added, and the platesallowed to develop for 5-15 minutes. The reaction is stopped with 50microliter/well 1M H₃PO₄ and read at OD450. A culture is consideredpositive if it measured at least 50 pg of IFN-gamma/well abovebackground and is twice the background level of expression.

CTL Expansion.

Those cultures that demonstrate specific lytic activity againstpeptide-pulsed targets and/or tumor targets are expanded over a two weekperiod with anti-CD3. Briefly, 5×10⁴ CD8+ cells are added to a T25 flaskcontaining the following: 1×10⁶ irradiated (4,200 rad) PBMC (autologousor allogeneic) per ml, 2×10⁵ irradiated (8,000 rad) EBV-transformedcells per ml, and OKT3 (anti-CD3) at 30ng per ml in RPMI-1640 containing10% (v/v) human AB serum, non-essential amino acids, sodium pyruvate, 25μM 2-mercaptoethanol, L-glutamine and penicillin/streptomycin.Recombinant human IL2 is added 24 hours later at a final concentrationof 200 IU/ml and every three days thereafter with fresh media at 50IU/mi. The cells are split if the cell concentration exceeds 1×10⁶/mland the cultures are assayed between days 13 and 15 at E:T ratios of 30,10, 3 and 1:1 in the ⁵¹Cr release assay or at 1×10⁶/ml in the in situIFNγ assay using the same targets as before the expansion.

Cultures are expanded in the absence of anti-CD3, as follows. Thosecultures that demonstrate specific lytic activity against peptide andendogenous targets are selected and 5×10⁴ CD8+ cells are added to a T25flask containing the following: 1×10⁶ autologous PBMC per ml which havebeen peptide-pulsed with 10 μg/ml peptide for two hours at 37° C. andirradiated (4,200 rad); 2×10⁵ irradiated (8,000 rad) EBV-transformedcells per ml RPMI-1640 containing 10% (v/v) human AB serum,non-essential AA, sodium pyruvate, 25 mM 2-ME, L-glutamine andgentamicin.

Immunogenicity of A2 Supermotif-Bearing Peptides

A2-supermotif cross-reactive binding peptides are tested in the cellularassay for the ability to induce peptide-specific CTL in normalindividuals. In this analysis, a peptide is typically considered to bean epitope if it induces peptide-specific CTLs in at least individuals,and preferably, also recognizes the endogenously expressed peptide.

Immunogenicity can also be confirmed using PBMCs isolated from patientsbearing a tumor that expresses 98P4B6. Briefly, PBMCs are isolated frompatients, re-stimulated with peptide-pulsed monocytes and assayed forthe ability to recognize peptide-pulsed target cells as well astransfected cells endogenously expressing the antigen.

Evaluation of A*03/A11 Immunogenicity

HLA-A3 supermotif-bearing cross-reactive binding peptides are alsoevaluated for immunogenicity using methodology analogous for that usedto evaluate the immunogenicity of the HLA-A2 supermotif peptides.

Evaluation of B7 Immunogenicity

Immunogenicity screening of the B7-supertype cross-reactive bindingpeptides identified as set forth herein are confirmed in a manneranalogous to the confirmation of A2-and A3-supermotif-bearing peptides.

Peptides bearing other supermotifs/motifs, e.g., HLA-A1, HLA-A24 etc.are also confirmed using similar methodology.

Example 15 Implementation of the Extended Supermotif to Improve theBinding Capacity of Native Epitopes by Creating Analogs

HLA motifs and supermotifs (comprising primary and/or secondaryresidues) are useful in the identification and preparation of highlycross-reactive native peptides, as demonstrated herein. Moreover, thedefinition of HLA motifs and supermotifs also allows one to engineerhighly cross-reactive epitopes by identifying residues within a nativepeptide sequence which can be analoged to confer upon the peptidecertain characteristics, e.g. greater cross-reactivity within the groupof HLA molecules that comprise a supertype, and/or greater bindingaffinity for some or all of those HLA molecules. Examples of analogingpeptides to exhibit modulated binding affinity are set forth in thisexample.

Analoging at Primary Anchor Residues

Peptide engineering strategies are implemented to further increase thecross-reactivity of the epitopes. For example, the main anchors ofA2-supermotif-bearing peptides are altered, for example, to introduce apreferred L, I, V, or M at position 2, and I or V at the C-terminus.

To analyze the cross-reactivity of the analog peptides, each engineeredanalog is initially tested for binding to the prototype A2 supertypeallele A*0201, then, if A*0201 binding capacity is maintained, forA2-supertype cross-reactivity.

Alternatively, a peptide is confirmed as binding one or all supertypemembers and then analoged to modulate binding affinity to any one (ormore) of the supertype members to add population coverage.

The selection of analogs for immunogenicity in a cellular screeninganalysis is typically further restricted by the capacity of the parentwild type (WT) peptide to bind at least weakly, i.e., bind at an IC₅₀ of5000 nM or less, to three of more A2 supertype alleles. The rationalefor this requirement is that the WT peptides must be presentendogenously in sufficient quantity to be biologically relevant.Analoged peptides have been shown to have increased immunogenicity andcross-reactivity by T cells specific for the parent epitope (see, e.g.,Parkhurst et al., J. Immunol. 157:2539, 1996; and Pogue et al., Proc.Natl. Acad. Sci. USA 92:8166,1995).

In the cellular screening of these peptide analogs, it is important toconfirm that analog-specific CTLs are also able to recognize thewild-type peptide and, when possible, target cells that endogenouslyexpress the epitope.

Analoging of HLA-A3 and B7-Supermotif-Bearing Peptides

Analogs of HLA-A3 supermotif-bearing epitopes are generated usingstrategies similar to those employed in analoging HLA-A2supermotif-bearing peptides. For example, peptides binding to ⅗ of theA3-supertype molecules are engineered at primary anchor residues topossess a preferred residue (V, S, M, or A) at position 2.

The analog peptides are then tested for the ability to bind A*03 andA*11 (prototype A3 supertype alleles). Those peptides that demonstrate≦500 nM binding capacity are then confirmed as having A3-supertypecross-reactivity.

Similarly to the A2- and A3-motif bearing peptides, peptides binding 3or more B7-supertype alleles can be improved, where possible, to achieveincreased cross-reactive binding or greater binding affinity or bindinghalf life. B7 supermotif-bearing peptides are, for example, engineeredto possess a preferred residue (V, I, L, or F) at the C-terminal primaryanchor position, as demonstrated by Sidney et al. (J. Immunol.157:3480-3490, 1996).

Analoging at primary anchor residues of other motif and/orsupermotif-bearing epitopes is performed in a like manner.

The analog peptides are then be confirmed for immunogenicity, typicallyin a cellular screening assay. Again, it is generally important todemonstrate that analog-specific CTLs are also able to recognize thewild-type peptide and, when possible, targets that endogenously expressthe epitope.

Analoging at Secondary Anchor Residues

Moreover, HLA supermotifs are of value in engineering highlycross-reactive peptides and/or peptides that bind HLA molecules withincreased affinity by identifying particular residues at secondaryanchor positions that are associated with such properties. For example,the binding capacity of a B7 supermotif-bearing peptide with an Fresidue at position 1 is analyzed. The peptide is then analoged to, forexample, substitute L for F at position 1. The analoged peptide isevaluated for increased binding affinity, binding half life and/orincreased cross-reactivity. Such a procedure identifies analogedpeptides with enhanced properties.

Engineered analogs with sufficiently improved binding capacity orcross-reactivity can also be tested for immunogenicity inHLA-B7-transgenic mice, following for example, IFA immunization orlipopeptide immunization. Analoged peptides are additionally tested forthe ability to stimulate a recall response using PBMC from patients with98P4B6-expressing tumors.

Other Analoging Strategies

Another form of peptide analoging, unrelated to anchor positions,involves the substitution of a cysteine with α-amino butyric acid. Dueto its chemical nature, cysteine has the propensity to form disulfidebridges and sufficiently alter the peptide structurally so as to reducebinding capacity. Substitution of α-amino butyric acid for cysteine notonly alleviates this problem, but has been shown to improve binding andcrossbinding capabilities in some instances (see, e.g., the review bySette et al., In: Persistent Viral Infections, Eds. R. Ahmed and I.Chen, John Wiley & Sons, England, 1999).

Thus, by the use of single amino acid substitutions, the bindingproperties and/or cross-reactivity of peptide ligands for HLA supertypemolecules can be modulated.

Example 16 Identification and Confirmation of 98P4B6-Derived SequencesWith HLA-DR Binding Motifs

Peptide epitopes bearing an HLA class II supermotif or motif areidentified and confirmed as outlined below using methodology similar tothat described for HLA Class I peptides.

Selection of HLA-DR-Supermotif-Bearing Epitopes.

To identify 98P4B6-derived, HLA class II HTL epitopes, a 98P4B6 antigenis analyzed for the presence of sequences bearing an HLA-DR-motif orsupermotif. Specifically, 15-mer sequences are selected comprising aDR-supermotif, comprising a 9-mer core, and three-residue N- andC-terminal flanking regions (15 amino acids total).

Protocols for predicting peptide binding to DR molecules have beendeveloped (Southwood et al., J. Immunol. 160:3363-3373, 1998). Theseprotocols, specific for individual DR molecules, allow the scoring, andranking, of 9-mer core regions. Each protocol not only scores peptidesequences for the presence of DR-supermotif primary anchors (i.e., atposition 1 and position 6) within a 9-mer core, but additionallyevaluates sequences for the presence of secondary anchors. Usingallele-specific selection tables (see, e.g., Southwood et al., ibid.),it has been found that these protocols efficiently select peptidesequences with a high probability of binding a particular DR molecule.Additionally, it has been found that performing these protocols intandem, specifically those for DR1, DR4w4, and DR7, can efficientlyselect DR cross-reactive peptides.

The 98P4B6-derived peptides identified above are tested for theirbinding capacity for various common HLA-DR molecules. All peptides areinitially tested for binding to the DR molecules in the primary panel:DR1, DR4w4, and DR7. Peptides binding at least two of these three DRmolecules are then tested for binding to DR2w2 β1, DR2w2 β2, DR6w19, andDR9 molecules in secondary assays. Finally, peptides binding at leasttwo of the four secondary panel DR molecules, and thus cumulatively atleast four of seven different DR molecules, are screened for binding toDR4w15, DR5w11, and DR8w2 molecules in tertiary assays. Peptides bindingat least seven of the ten DR molecules comprising the primary,secondary, and tertiary screening assays are considered cross-reactiveDR binders. 98P4B6-derived peptides found to bind common HLA-DR allelesare of particular interest.

Selection of DR3 Motif Peptides

Because HLA-DR3 is an allele that is prevalent in Caucasian, Black, andHispanic populations, DR3 binding capacity is a relevant criterion inthe selection of HTL epitopes. Thus, peptides shown to be candidates mayalso be assayed for their DR3 binding capacity. However, in view of thebinding specificity of the DR3 motif, peptides binding only to DR3 canalso be considered as candidates for inclusion in a vaccine formulation.

To efficiently identify peptides that bind DR3, target 98P4B6 antigensare analyzed for sequences carrying one of the two DR3-specific bindingmotifs reported by Geluk et al. (J. Immunol. 152:5742-5748, 1994). Thecorresponding peptides are then synthesized and confirmed as having theability to bind DR3 with an affinity of 1 μM or better, i.e., less than1 μM. Peptides are found that meet this binding criterion and qualify asHLA class II high affinity binders.

DR3 binding epitopes identified in this manner are included in vaccinecompositions with DR supermotif-bearing peptide epitopes.

Similarly to the case of HLA class I motif-bearing peptides, the classII motif-bearing peptides are analoged to improve affinity orcross-reactivity. For example, aspartic acid at position 4 of the 9-mercore sequence is an optimal residue for DR3 binding, and substitutionfor that residue often improves DR 3 binding.

Example 17 Immunogenicity of 98P4B6-Derived HTL Epitopes

This example determines immunogenic DR supermotif- and DR3 motif-bearingepitopes among those identified using the methodology set forth herein.

Immunogenicity of HTL epitopes are confirmed in a manner analogous tothe determination of immunogenicity of CTL epitopes, by assessing theability to stimulate HTL responses and/or by using appropriatetransgenic mouse models. Immunogenicity is determined by screening for:1.) in vitro primary induction using normal PBMC or 2.) recall responsesfrom patents who have 98P4B6-expressing tumors.

Example 18 Calculation of Phenotypic Frequencies of HLA-Supertypes inVarious Ethnic Backgrounds to Determine Breadth of Population Coverage

This example illustrates the assessment of the breadth of populationcoverage of a vaccine composition comprised of multiple epitopescomprising multiple supermotifs and/or motifs.

In order to analyze population coverage, gene frequencies of HLA allelesare determined. Gene frequencies for each HLA allele are calculated fromantigen or allele frequencies utilizing the binomial distributionformulae gf=1-(SQRT(1−af)) (see, e.g., Sidney et al., Human Immunol.45:79-93,1996). To obtain overall phenotypic frequencies, cumulativegene frequencies are calculated, and the cumulative antigen frequenciesderived by the use of the inverse formula [af=1−-(1−Cgf)²].

Where frequency data is not available at the level of DNA typing,correspondence to the serologically defined antigen frequencies isassumed. To obtain total potential supertype population coverage nolinkage disequilibrium is assumed, and only alleles confirmed to belongto each of the supertypes are included (minimal estimates). Estimates oftotal potential coverage achieved by inter-loci combinations are made byadding to the A coverage the proportion of the non-A covered populationthat could be expected to be covered by the B alleles considered (e.g.,total=A+B*(1−A)). Confirmed members of the A3-like supertype are A3,A11, A31, A*3301, and A*6801. Although the A3-like supertype may alsoinclude A34, A66, and A*7401, these alleles were not included in overallfrequency calculations. Likewise, confirmed members of the A2-likesupertype family are A*0201, A*0202, A*0203, A*0204, A*0205, A*0206,A*0207, A*6802, and A*6901. Finally, the B7-like supertype-confirmedalleles are: B7, B*3501-03, B51, B*5301, B*5401, B*5501-2, B*5601,B*6701, and B*7801 (potentially also B*1401, B*3504-06, B*4201, andB*5602).

Population coverage achieved by combining the A2-, A3- and B7-supertypesis approximately 86% in five major ethnic groups. Coverage may beextended by including peptides bearing the Al and A24 motifs. Onaverage, A1 is present in 12% and A24 in 29% of the population acrossfive different major ethnic groups (Caucasian, North American Black,Chinese, Japanese, and Hispanic). Together, these alleles arerepresented with an average frequency of 39% in these same ethnicpopulations. The total coverage across the major ethnicities when Al andA24 are combined with the coverage of the A2-, A3- and B7-supertypealleles is >95%, see, e.g., Table IV (G). An analogous approach can beused to estimate population coverage achieved with combinations of classII motif-bearing epitopes.

Immunogenicity studies in humans (e.g., Bertoni et al., J. Clin. Invest.100:503, 1997; Doolan et al., Immunity 7:97, 1997; and Threlkeld et al.,J. Immunol. 159:1648, 1997) have shown that highly cross-reactivebinding peptides are almost always recognized as epitopes. The use ofhighly cross-reactive binding peptides is an important selectioncriterion in identifying candidate epitopes for inclusion in a vaccinethat is immunogenic in a diverse population.

With a sufficient number of epitopes (as disclosed herein and from theart), an average population coverage is predicted to be greater than 95%in each of five major ethnic populations. The game theory Monte Carlosimulation analysis, which is known in the art (see e.g., Osborne, M. J.and Rubinstein, A. “A course in game theory” MIT Press, 1994), can beused to estimate what percentage of the individuals in a populationcomprised of the Caucasian, North American Black, Japanese, Chinese, andHispanic ethnic groups would recognize the vaccine epitopes describedherein. A preferred percentage is 90%. A more preferred percentage is95%.

Example 19 CTL Recognition Of Endogenously Processed Antigens AfterPriming

This example confirms that CTL induced by native or analoged peptideepitopes identified and selected as described herein recognizeendogenously synthesized, i.e., native antigens.

Effector cells isolated from transgenic mice that are immunized withpeptide epitopes, for example HLA-A2 supermotif-bearing epitopes, arere-stimulated in vitro using peptide-coated stimulator cells. Six dayslater, effector cells are assayed for cytotoxicity and the cell linesthat contain peptide-specific cytotoxic activity are furtherre-stimulated. An additional six days later, these cell lines are testedfor cytotoxic activity on ⁵¹Cr labeled Jurkat-A2.1/K^(b) target cells inthe absence or presence of peptide, and also tested on ⁵¹Cr labeledtarget cells bearing the endogenously synthesized antigen, i.e. cellsthat are stably transfected with 98P4B6 expression vectors.

The results demonstrate that CTL lines obtained from animals primed withpeptide epitope recognize endogenously synthesized 98P4B6 antigen. Thechoice of transgenic mouse model to be used for such an analysis dependsupon the epitope(s) that are being evaluated. In addition toHLA-A*0201/K^(b) transgenic mice, several other transgenic mouse modelsincluding mice with human A11, which may also be used to evaluate A3epitopes, and B7 alleles have been characterized and others (e.g.,transgenic mice for HLA-A1 and A24) are being developed. HLA-DR1 andHLA-DR3 mouse models have also been developed, which may be used toevaluate HTL epitopes.

Example 20 Activity of CTL-HTL Conjugated Epitopes in Transgenic Mice

This example illustrates the induction of CTLs and HTLs in transgenicmice, by use of a 98P4B6-derived CTL and HTL peptide vaccinecompositions. The vaccine composition used herein comprise peptides tobe administered to a patient with a 98P4B6-expressing tumor. The peptidecomposition can comprise multiple CTL and/or HTL epitopes. The epitopesare identified using methodology as described herein. This example alsoillustrates that enhanced immunogenicity can be achieved by inclusion ofone or more HTL epitopes in a CTL vaccine composition; such a peptidecomposition can comprise an HTL epitope conjugated to a CTL epitope. TheCTL epitope can be one that binds to multiple HLA family members at anaffinity of 500 nM or less, or analogs of that epitope. The peptides maybe lipidated, if desired.

Immunization procedures: Immunization of transgenic mice is performed asdescribed (Alexander et al., J. Immunol. 159:4753-4761,1997). Forexample, A2/K^(b) mice, which are transgenic for the human HLAA2.1allele and are used to confirm the immunogenicity of HLA-A*0201 motif-or HLA-A2 supermotif-bearing epitopes, and are primed subcutaneously(base of the tail) with a 0.1 ml of peptide in Incomplete Freund'sAdjuvant, or if the peptide composition is a lipidated CTU/HTLconjugate, in DMSO/saline, or if the peptide composition is apolypeptide, in PBS or Incomplete Freund's Adjuvant. Seven days afterpriming, splenocytes obtained from these animals are restimulated withsyngenic irradiated LPS-activated lymphoblasts coated with peptide.

Cell lines: Target cells for peptide-specific cytotoxicity assays areJurkat cells transfected with the HLA-A2.1/K^(b) chimeric gene (e.g.,Vitiello et al., J. Exp. Med. 173:1007,1991)

In vitro CTL activation: One week after priming, spleen cells (30×10⁶cells/flask) are co-cultured at 37° C. with syngeneic, irradiated (3000rads), peptide coated lymphoblasts (10×10⁶ cells/flask) in 10 ml ofculture medium/T25 flask. After six days, effector cells are harvestedand assayed for cytotoxic activity.

Assay for cytotoxic activity: Target cells (1.0 to 1.5×106) areincubated at 37° C. in the presence of 200 μl of ⁵¹Cr. After 60 minutes,cells are washed three times and resuspended in R10 medium. Peptide isadded where required at a concentration of 1 μg/ml. For the assay, 10⁴⁵¹Cr-labeled target cells are added to different concentrations ofeffector cells (final volume of 200 μl) in U-bottom 96-well plates.After a six hour incubation period at 37° C., a 0.1 ml aliquot ofsupernatant is removed from each well and radioactivity is determined ina Micromedic automatic gamma counter. The percent specific lysis isdetermined by the formula: percent specific release=100×(experimentalrelease−spontaneous release)/(maximum release−spontaneous release). Tofacilitate comparison between separate CTL assays run under the sameconditions, % ⁵¹Cr release data is expressed as lytic units/10⁶ cells.One lytic unit is arbitrarily defined as the number of effector cellsrequired to achieve 30% lysis of 10,000 target cells in a six hour ⁵¹Crrelease assay. To obtain specific lytic units/10⁶, the lytic units/10⁶obtained in the absence of peptide is subtracted from the lyticunits/10⁶ obtained in the presence of peptide. For example, if 30% ⁵¹Crrelease is obtained at the effector (E): target (T) ratio of 50:1 (i.e.,5×10⁵ effector cells for 10,000 targets) in the absence of peptide and5:1 (i.e., 5×10⁴ effector cells for 10,000 targets) in the presence ofpeptide, the specific lytic units would be:[(1/50,000)−(1/500,000)]×10⁶=18 LU.

The results are analyzed to assess the magnitude of the CTL responses ofanimals injected with the immunogenic CTUHTL conjugate vaccinepreparation and are compared to the magnitude of the CTL responseachieved using, for example, CTL epitopes as outlined above in theExample entitled “Confirmation of Immunogenicity.” Analyses similar tothis may be performed to confirm the immunogenicity of peptideconjugates containing multiple CTL epitopes and/or multiple HTLepitopes. In accordance with these procedures, it is found that a CTLresponse is induced, and concomitantly that an HTL response is inducedupon administration of such compositions.

Example 21 Selection of CTL and HTL Epitopes for Inclusion in a98P4B6-Specific Vaccine.

This example illustrates a procedure for selecting peptide epitopes forvaccine compositions of the invention. The peptides in the compositioncan be in the form of a nucleic acid sequence, either single or one ormore sequences (i.e., minigene) that encodes peptide(s), or can besingle and/or polyepitopic peptides.

The following principles are utilized when selecting a plurality ofepitopes for inclusion in a vaccine composition. Each of the followingprinciples is balanced in order to make the selection.

Epitopes are selected which, upon administration, mimic immune responsesthat are correlated with 98P4B6 clearance. The number of epitopes useddepends on observations of patients who spontaneously clear 98P4B6. Forexample, if it has been observed that patients who spontaneously clear98P4B6-expressing cells generate an immune response to at least three(3) epitopes from 98P4B6 antigen, then at least three epitopes should beincluded for HLA class I. A similar rationale is used to determine HLAclass II epitopes.

Epitopes are often selected that have a binding affinity of an IC₅₀ of500 nM or less for an HLA class I molecule, or for class II, an IC₅₀ of1000 nM or less; or HLA Class I peptides with high binding scores fromthe BIMAS web site.

In order to achieve broad coverage of the vaccine through out a diversepopulation, sufficient supermotif bearing peptides, or a sufficientarray of allele-specific motif bearing peptides, are selected to givebroad population coverage. In one embodiment, epitopes are selected toprovide at least 80% population coverage. A Monte Carlo analysis, astatistical evaluation known in the art, can be employed to assessbreadth, or redundancy, of population coverage.

When creating polyepitopic compositions, or a minigene that encodessame, it is typically desirable to generate the smallest peptidepossible that encompasses the epitopes of interest. The principlesemployed are similar, if not the same, as those employed when selectinga peptide comprising nested epitopes. For example, a protein sequencefor the vaccine composition is selected because it has maximal number ofepitopes contained within the sequence, i.e., it has a highconcentration of epitopes. Epitopes may be nested or overlapping (i.e.,frame shifted relative to one another). For example, with overlappingepitopes, two 9-mer epitopes and one 10-mer epitope can be present in a10 amino acid peptide. Each epitope can be exposed and bound by an HLAmolecule upon administration of such a peptide. A multi-epitopic,peptide can be generated synthetically, recombinantly, or via cleavagefrom the native source. Alternatively, an analog can be made of thisnative sequence, whereby one or more of the epitopes comprisesubstitutions that alter the cross-reactivity and/or binding affinityproperties of the polyepitopic peptide. Such a vaccine composition isadministered for therapeutic or prophylactic purposes. This embodimentprovides for the possibility that an as yet undiscovered aspect ofimmune system processing will apply to the native nested sequence andthereby facilitate the production of therapeutic or prophylactic immuneresponse-inducing vaccine compositions. Additionally such an embodimentprovides for the possibility of motif-bearing epitopes for an HLA makeupthat is presently unknown. Furthermore, this embodiment (absent thecreating of any analogs) directs the immune response to multiple peptidesequences that are actually present in 98P4B6, thus avoiding the need toevaluate any junctional epitopes. Lastly, the embodiment provides aneconomy of scale when producing nucleic acid vaccine compositions.Related to this embodiment, computer programs can be derived inaccordance with principles in the art, which identify in a targetsequence, the greatest number of epitopes per sequence length.

A vaccine composition comprised of selected peptides, when administered,is safe, efficacious, and elicits an immune response similar inmagnitude to an immune response that controls or clears cells that bearor overexpress 98P4B6.

Example 22 Construction of “Minigene” Multi-Epitope DNA Plasmids

This example discusses the construction of a minigene expressionplasmid. Minigene plasmids may, of course, contain variousconfigurations of B cell, CTL and/or HTL epitopes or epitope analogs asdescribed herein.

A minigene expression plasmid typically includes multiple CTL and HTLpeptide epitopes. In the present example, HLA-A2,-A3,-B7supermotif-bearing peptide epitopes and HLA-A1 and -A24 motif-bearingpeptide epitopes are used in conjunction with DR supermotif-bearingepitopes and/or DR3 epitopes. HLA class I supermotif or motif-bearingpeptide epitopes derived 98P4B6, are selected such that multiplesupermotifs/motifs are represented to ensure broad population coverage.Similarly, HLA class II epitopes are selected from 98P4B6 to providebroad population coverage, i.e. both HLA DR-1-4-7 supermotif-bearingepitopes and HLA DR-3 motif-bearing epitopes are selected for inclusionin the minigene construct. The selected CTL and HTL epitopes are thenincorporated into a minigene for expression in an expression vector.

Such a construct may additionally include sequences that direct the HTLepitopes to the endoplasmic reticulum. For example, the II protein maybe fused to one or more HTL epitopes as described in the art, whereinthe CLIP sequence of the II protein is removed and replaced with an HLAclass II epitope sequence so that HLA class II epitope is directed tothe endoplasmic reticulum, where the epitope binds to an HLA class IImolecules.

This example illustrates the methods to be used for construction of aminigene-bearing expression plasmid. Other expression vectors that maybe used for minigene compositions are available and known to those ofskill in the art.

The minigene DNA plasmid of this example contains a consensus Kozaksequence and a consensus murine kappa Ig-light chain signal sequencefollowed by CTL and/or HTL epitopes selected in accordance withprinciples disclosed herein. The sequence encodes an open reading framefused to the Myc and His antibody epitope tag coded for by the pcDNA 3.1Myc-His vector.

Overlapping oligonucleotides that can, for example, average about 70nucleotides in length with 15 nucleotide overlaps, are synthesized andHPLC-purified. The oligonucleotides encode the selected peptide epitopesas well as appropriate linker nucleotides, Kozak sequence, and signalsequence. The final multiepitope minigene is assembled by extending theoverlapping oligonucleotides in three sets of reactions using PCR. APerkin/Elmer 9600 PCR machine is used and a total of 30 cycles areperformed using the following conditions: 95° C. for 15 sec, annealingtemperature (5° below the lowest calculated Tm of each primer pair) for30 sec, and 72° C. for 1 min.

For example, a minigene is prepared as follows. For a first PCRreaction, 5 μg of each of two oligonucleotides are annealed andextended: In an example using eight oligonucleotides, i.e., four pairsof primers, oligonucleotides 1+2, 3+4, 5+6, and 7+8 are combined in 100μl reactions containing Pfu polymerase buffer (1×=10 mM KCL, 10 mM(NH4)₂SO₄, 20 mM Tris-chloride, pH 8.75, 2 mM MgSO₄, 0.1% Triton X-100,100 μg/ml BSA), 0.25 mM each dNTP, and 2.5 U of Pfu polymerase. Thefull-length dimer products are gel-purified, and two reactionscontaining the product of 1+2 and 3+4, and the product of 5+6 and 7+8are mixed, annealed, and extended for 10 cycles. Half of the tworeactions are then mixed, and 5 cycles of annealing and extensioncarried out before flanking primers are added to amplify the full lengthproduct. The full-length product is gel-purified and cloned intopCR-blunt (Invitrogen) and individual clones are screened by sequencing.

Example 23 The Plasmid Construct and the Degree to Which It InducesImmunogenicity.

The degree to which a plasmid construct, for example a plasmidconstructed in accordance with the previous Example, is able to induceimmunogenicity is confirmed in vitro by determining epitope presentationby APC following transduction or transfection of the APC with anepitope-expressing nucleic acid construct. Such a study determines“antigenicity” and allows the use of human APC. The assay determines theability of the epitope to be presented by the APC in a context that isrecognized by a T cell by quantifying the density of epitope-HLA class Icomplexes on the cell surface. Quantitation can be performed by directlymeasuring the amount of peptide eluted from the APC (see, e.g., Sijts etal., J. Immunol. 156:683-692, 1996; Demotz et al., Nature 342:682-684,1989); or the number of peptide-HLA class I complexes can be estimatedby measuring the amount of lysis or lymphokine release induced bydiseased or transfected target cells, and then determining theconcentration of peptide necessary to obtain equivalent levels of lysisor lymphokine release (see, e.g., Kageyama et al., J. Immunol.154:567-576,1995).

Alternatively, immunogenicity is confirmed through in vivo injectionsinto mice and subsequent in vitro assessment of CTL and HTL activity,which are analyzed using cytotoxicity and proliferation assays,respectively, as detailed e.g., in Alexander et al., Immunity 1:751-761,1994.

For example, to confirm the capacity of a DNA minigene constructcontaining at least one HLA-A2 supermotif peptide to induce CTLs invivo, HLA-A2.1/K^(b) transgenic mice, for example, are immunizedintramuscularly with 100 μg of naked cDNA. As a means of comparing thelevel of CTLs induced by cDNA immunization, a control group of animalsis also immunized with an actual peptide composition that comprisesmultiple epitopes synthesized as a single polypeptide as they would beencoded by the minigene.

Splenocytes from immunized animals are stimulated twice with each of therespective compositions (peptide epitopes encoded in the minigene or thepolyepitopic peptide), then assayed for peptide-specific cytotoxicactivity in a ⁵¹Cr release assay. The results indicate the magnitude ofthe CTL response directed against the A2-restricted epitope, thusindicating the in vivo immunogenicity of the minigene vaccine andpolyepitopic vaccine.

It is, therefore, found that the minigene elicits immune responsesdirected toward the HLA-A2 supermotif peptide epitopes as does thepolyepitopic peptide vaccine. A similar analysis is also performed usingother HLA-A3 and HLA-B7 transgenic mouse models to assess CTL inductionby HLA-A3 and HLA-B7 motif or supermotif epitopes, whereby it is alsofound that the minigene elicits appropriate immune responses directedtoward the provided epitopes.

To confirm the capacity of a class II epitope-encoding minigene toinduce HTLs in vivo, DR transgenic mice, or for those epitopes thatcross react with the appropriate mouse MHC molecule, I-A^(b)-restrictedmice, for example, are immunized intramuscularly with 100 μg of plasmidDNA. As a means of comparing the level of HTLs induced by DNAimmunization, a group of control animals is also immunized with anactual peptide composition emulsified in complete Freund's adjuvant.CD4+ T cells, i.e. HTLs, are purified from splenocytes of immunizedanimals and stimulated with each of the respective compositions(peptides encoded in the minigene). The HTL response is measured using a³H-thymidine incorporation proliferation assay, (see, e.g., Alexander etal. Immunity 1:751-761, 1994). The results indicate the magnitude of theHTL response, thus demonstrating the in vivo immunogenicity of theminigene.

DNA minigenes, constructed as described in the previous Example, canalso be confirmed as a vaccine in combination with a boosting agentusing a prime boost protocol. The boosting agent can consist ofrecombinant protein (e.g., Barnett et al., Aids Res. and HumanRetroviruses 14, Supplement 3:S299-S309, 1998) or recombinant vaccinia,for example, expressing a minigene or DNA encoding the complete proteinof interest (see, e.g., Hanke et al., Vaccine 16:439-445, 1998; Sedegahet al., Proc. Natl. Acad. Sci USA 95:7648-53, 1998; Hanke and McMichael,Immunol. Letters 66:177-181, 1999; and Robinson et al., Nature Med.5:526-34, 1999).

For example, the efficacy of the DNA minigene used in a prime boostprotocol is initially evaluated in transgenic mice. In this example,A2.1/K^(b) transgenic mice are immunized IM with 100 μg of a DNAminigene encoding the immunogenic peptides including at least one HLA-A2supermotif-beating peptide. After an incubation period (ranging from 3-9weeks), the mice are boosted IP with 10⁷ pfu/mouse of a recombinantvaccinia virus expressing the same sequence encoded by the DNA minigene.Control mice are immunized with 100 μg of DNA or recombinant vacciniawithout the minigene sequence, or with DNA encoding the minigene, butwithout the vaccinia boost. After an additional incubation period of twoweeks, splenocytes from the mice are immediately assayed forpeptide-specific activity in an ELISPOT assay. Additionally, splenocytesare stimulated in vitro with the A2-restricted peptide epitopes encodedin the minigene and recombinant vaccinia, then assayed forpeptide-specific activity in an alpha, beta and/or gamma IFN ELISA.

It is found that the minigene utilized in a prime-boost protocol elicitsgreater immune responses toward the HLA-A2 supermotif peptides than withDNA alone. Such an analysis can also be performed using HLA-A11 orHLA-B7 transgenic mouse models to assess CTL induction by HLA-A3 orHLA-B7 motif or supermotif epitopes. The use of prime boost protocols inhumans is described below in the Example entitled “Induction of CTLResponses Using a Prime Boost Protocol.”

Example 24 Peptide Compositions for Prophylactic Uses

Vaccine compositions of the present invention can be used to prevent98P4B6 expression in persons who are at risk for tumors that bear thisantigen. For example, a polyepitopic peptide epitope composition (or anucleic acid comprising the same) containing multiple CTL and HTLepitopes such as those selected in the above Examples, which are alsoselected to target greater than 80% of the population, is administeredto individuals at risk for a 98P4B6-associated tumor.

For example, a peptide-based composition is provided as a singlepolypeptide that encompasses multiple epitopes. The vaccine is typicallyadministered in a physiological solution that comprises an adjuvant,such as Incomplete Freunds Adjuvant. The dose of peptide for the initialimmunization is from about 1 to about 50,000 μg, generally 100-5,000 μg,for a 70 kg patient. The initial administration of vaccine is followedby booster dosages at 4 weeks followed by evaluation of the magnitude ofthe immune response in the patient, by techniques that determine thepresence of epitope-specific CTL populations in a PBMC sample.Additional booster doses are administered as required. The compositionis found to be both safe and efficacious as a prophylaxis against98P4B6-associated disease.

Alternatively, a composition typically comprising transfecting agents isused for the administration of a nucleic acid-based vaccine inaccordance with methodologies known in the art and disclosed herein.

Example 25 Polyepitopic Vaccine Compositions Derived from Native 98P4B6Sequences

A native 98P4B6 polyprotein sequence is analyzed, preferably usingcomputer algorithms defined for each class I and/or class II supermotifor motif, to identify “relatively short” regions of the polyprotein thatcomprise multiple epitopes. The “relatively short” regions arepreferably less in length than an entire native antigen. This relativelyshort sequence that contains multiple distinct or overlapping, “nested”epitopes can be used to generate a minigene construct. The construct isengineered to express the peptide, which corresponds to the nativeprotein sequence. The “relatively short” peptide is generally less than250 amino acids in length, often less than 100 amino acids in length,preferably less than 75 amino acids in length, and more preferably lessthan 50 amino acids in length. The protein sequence of the vaccinecomposition is selected because it has maximal number of epitopescontained within the sequence, i.e., it has a high concentration ofepitopes. As noted herein, epitope motifs may be nested or overlapping(i.e., frame shifted relative to one another). For example, withoverlapping epitopes, two 9-mer epitopes and one 1 mer epitope can bepresent in a 10 amino acid peptide. Such a vaccine composition isadministered for therapeutic or prophylactic purposes.

The vaccine composition will include, for example, multiple CTL epitopesfrom 98P4B6 antigen and at least one HTL epitope. This polyepitopicnative sequence is administered either as a peptide or as a nucleic acidsequence which encodes the peptide. Alternatively, an analog can be madeof this native sequence, whereby one or more of the epitopes comprisesubstitutions that alter the cross-reactivity and/or binding affinityproperties of the polyepitopic peptide.

The embodiment of this example provides for the possibility that an asyet undiscovered aspect of immune system processing will apply to thenative nested sequence and thereby facilitate the production oftherapeutic or prophylactic immune response-inducing vaccinecompositions. Additionally, such an embodiment provides for thepossibility of motif-bearing epitopes for an HLA makeup(s) that ispresently unknown. Furthermore, this embodiment (excluding an analogedembodiment) directs the immune response to multiple peptide sequencesthat are actually present in native 98P4B6, thus avoiding the need toevaluate any junctional epitopes. Lastly, the embodiment provides aneconomy of scale when producing peptide or nucleic acid vaccinecompositions.

Related to this embodiment, computer programs are available in the artwhich can be used to identify in a target sequence, the greatest numberof epitopes per sequence length.

Example 26 Polyepitopic Vaccine Compositions from Multiple Antigens

The 98P4B6 peptide epitopes of the present invention are used inconjunction with epitopes from other target tumor-associated antigens,to create a vaccine composition that is useful for the prevention ortreatment of cancer that expresses 98P4B6 and such other antigens. Forexample, a vaccine composition can be provided as a single polypeptidethat incorporates multiple epitopes from 98P4B6 as well astumor-associated antigens that are often expressed with a target cancerassociated with 98P4B6 expression, or can be administered as acomposition comprising a cocktail of one or more discrete epitopes.Alternatively, the vaccine can be administered as a minigene constructor as dendritic cells which have been loaded with the peptide epitopesin vitro.

Example 27 Use of Peptides to Evaluate an Immune Response

Peptides of the invention may be used to analyze an immune response forthe presence of specific antibodies, CTL or HTL directed to 98P4B6. Suchan analysis can be performed in a manner described by Ogg et al.,Science 279:2103-2106, 1998. In this Example, peptides in accordancewith the invention are used as a reagent for diagnostic or prognosticpurposes, not as an immunogen.

In this example highly sensitive human leukocyte antigen tetramericcomplexes (“tetramers”) are used for a cross-sectional analysis of, forexample, 98P4B6 HLA-A*0201-specific CTL frequencies from HLAA*0201-positive individuals at different stages of disease or followingimmunization comprising a 98P4B6 peptide containing an A*0201 motif.Tetrameric complexes are synthesized as described (Musey et al., N.Engl. J. Med. 337:1267, 1997). Briefly, purified HLA heavy chain (A*0201in this example) and β2-microglobulin are synthesized by means of aprokaryotic expression system. The heavy chain is modified by deletionof the transmembrane-cytosolic tail and COOH-terminal addition of asequence containing a BirA enzymatic biotinylation site. The heavychain, β2-microglobulin, and peptide are refolded by dilution. The 45-kDrefolded product is isolated by fast protein liquid chromatography andthen biotinylated by BirA in the presence of biolin (Sigma, St. Louis,Mo.), adenosine 5′ triphosphate and magnesium.Streptavidin-phycoerythrin conjugate is added in a 1:4 molar ratio, andthe tetrameric product is concentrated to 1 mg/ml. The resulting productis referred to as tetramer-phycoerythrin.

For the analysis of patient blood samples, approximately one millionPBMCs are centrifuged at 300 g for 5 minutes and resuspended in 50 μl ofcold phosphate-buffered saline. Tri-color analysis is performed with thetetramer-phycoerythrin, along with anti-CD8-Tricolor, and anti-CD38. ThePBMCs are incubated with tetramer and antibodies on ice for 30 to 60 minand then washed twice before formaldehyde fixation. Gates are applied tocontain >99.98% of control samples. Controls for the tetramers includeboth A*0201-negative individuals and A*0201-positive non-diseaseddonors. The percentage of cells stained with the tetramer is thendetermined by flow cytometry. The results indicate the number of cellsin the PBMC sample that contain epitope-restricted CTLs, thereby readilyindicating the extent of immune response to the 98P4B6 epitope, and thusthe status of exposure to 98P4B6, or exposure to a vaccine that elicitsa protective or therapeutic response.

Example 28 Use of Peptide Epitopes to Evaluate Recall Responses

The peptide epitopes of the invention are used as reagents to evaluate Tcell responses, such as acute or recall responses, in patients. Such ananalysis may be performed on patients who have recovered from98P4B6-associated disease or who have been vaccinated with a 98P4B6vaccine.

For example, the class I restricted CTL response of persons who havebeen vaccinated may be analyzed. The vaccine may be any 98P4B6 vaccine.PBMC are collected from vaccinated individuals and HLA typed.Appropriate peptide epitopes of the invention that, optimally, bearsupermotifs to provide cross-reactivity with multiple HLA supertypefamily members, are then used for analysis of samples derived fromindividuals who bear that HLA type.

PBMC from vaccinated individuals are separated on Ficoll-Histopaquedensity gradients (Sigma Chemical Co., St. Louis, Mo.), washed threetimes in HBSS (GIBCO Laboratories), resuspended in RPMI-1640 (GIBCOLaboratories) supplemented with L-glutamine (2 mM), penicillin (50U/ml), streptomycin (50 μg/ml), and Hepes (10 mM) containing 10%heat-inactivated human AB serum (complete RPMI) and plated usingmicroculture formats. A synthetic peptide comprising an epitope of theinvention is added at 10 μg/ml to each well and HBV core 128-140 epitopeis added at 1 μg/ml to each well as a source of T cell help during thefirst week of stimulation.

In the microculture format, 4×10 ⁵ PBMC are stimulated with peptide in 8replicate cultures in 96-well round bottom plate in 100 μl/well ofcomplete RPMI. On days 3 and 10, 100 μl of complete RPMI and 20 U/mlfinal concentration of rlL-2 are added to each well. On day 7 thecultures are transferred into a 96-well flat-bottom plate andrestimulated with peptide, rlL-2 and 105 irradiated (3,000 rad)autologous feeder cells. The cultures are tested for cytotoxic activityon day 14. A positive CTL response requires two or more of the eightreplicate cultures to display greater than 10% specific ⁵¹Cr release,based on comparison with non-diseased control subjects as previouslydescribed (Rehermann, et al., Nature Med. 2:1104,1108, 1996; Rehermannet al., J. Clin. Invest. 97:1655-1665, 1996; and Rehermann et al. J.Clin. Invest. 98:1432-1440,1996).

Target cell lines are autologous and allogeneic EBV-transformed B-LCLthat are either purchased from the American Society forHistocompatibility and Immunogenetics (ASH I, Boston, Mass.) orestablished from the pool of patients as described (Guilhot, et al. J.Virol. 66:2670-2678, 1992).

Cytotoxicity assays are performed in the following manner. Target cellsconsist of either allogeneic HLA-matched or autologous EBV-transformed Blymphoblastoid cell line that are incubated overnight with the syntheticpeptide epitope of the invention at 10 μM, and labeled with 100 μCi of⁵¹Cr (Amersham Corp., Arlington Heights, Ill.) for 1 hour after whichthey are washed four times with HBSS.

Cytolytic activity is determined in a standard 4-h, split well ⁵¹Crrelease assay using U-bottomed 96 well plates containing 3,000targets/well. Stimulated PBMC are tested at effector/target (E/T) ratiosof 20-50:1 on day 14. Percent cytotoxicity is determined from theformula: 100×[(experimental release−spontaneous release)/maximumrelease−spontaneous release)]. Maximum release is determined by lysis oftargets by detergent (2% Triton X-100; Sigma Chemical Co., St. Louis,Mo.). Spontaneous release is <25% of maximum release for allexperiments.

The results of such an analysis indicate the extent to whichHLA-restricted CTL populations have been stimulated by previous exposureto 98P4B6 or a 98P4B6 vaccine.

Similarly, Class II restricted HTL responses may also be analyzed.Purified PBMC are cultured in a 96-well flat bottom plate at a densityof 1.5×10⁵ cells/well and are stimulated with 10 μg/ml synthetic peptideof the invention, whole 98P4B6 antigen, or PHA. Cells are routinelyplated in replicates of 4-6 wells for each condition. After seven daysof culture, the medium is removed and replaced with fresh mediumcontaining 10 U/ml IL-2. Two days later, 1 μCi ³H-thymidine is added toeach well and incubation is continued for an additional 18 hours.Cellular DNA is then harvested on glass fiber mats and analyzed for³H-thymidine incorporation. Antigen-specific T cell proliferation iscalculated as the ratio of ³H-thymidine incorporation in the presence ofantigen divided by the ³H-thymidine incorporation in the absence ofantigen.

Example 29 Induction Of Specific CTL Response In Humans

A human clinical trial for an immunogenic composition comprising CTL andHTL epitopes of the invention is set up as an IND Phase I, doseescalation study and carried out as a randomized, double-blind,placebo-controlled trial. Such a trial is designed, for example, asfollows:

A total of about 27 individuals are enrolled and divided into 3 groups:

Group I: 3 subjects are injected with placebo and 6 subjects areinjected with 5 μg of peptide composition;

Group II: 3 subjects are injected with placebo and 6 subjects areinjected with 50 μg peptide composition;

Group III: 3 subjects are injected with placebo and 6 subjects areinjected with 500 μg of peptide composition.

After 4 weeks following the first injection, all subjects receive abooster inoculation at the same dosage.

The endpoints measured in this study relate to the safety andtolerability of the peptide composition as well as its immunogenicity.Cellular immune responses to the peptide composition are an index of theintrinsic activity of this the peptide composition, and can therefore beviewed as a measure of biological efficacy. The following summarize theclinical and laboratory data that relate to safety and efficacyendpoints.

Safety: The incidence of adverse events is monitored in the placebo anddrug treatment group and assessed in terms of degree and reversibility.

Evaluation of Vaccine Efficacy: For evaluation of vaccine efficacy,subjects are bled before and after injection. Peripheral bloodmononuclear cells are isolated from fresh heparinized blood byFicoll-Hypaque density gradient centrifugation, aliquoted in freezingmedia and stored frozen. Samples are assayed for CTL and HTL activity.

The vaccine is found to be both safe and efficacious.

Example 30 Phase II Trials In Patients Expressing 98P4B6

Phase II trials are performed to study the effect of administering theCTL-HTL peptide compositions to patients having cancer that expresses98P4B6. The main objectives of the trial are to determine an effectivedose and regimen for inducing CTLs in cancer patients that express98P4B6, to establish the safety of inducing a CTL and HTL response inthese patients, and to see to what extent activation of CTLs improvesthe clinical picture of these patients, as manifested, e.g., by thereduction and/or shrinking of lesions. Such a study is designed, forexample, as follows:

The studies are performed in multiple centers. The trial design is anopen-label, uncontrolled, dose escalation protocol wherein the peptidecomposition is administered as a single dose followed six weeks later bya single booster shot of the same dose. The dosages are 50, 500 and5,000 micrograms per injection. Drug-associated adverse effects(severity and reversibility) are recorded.

There are three patient groupings. The first group is injected with 50micrograms of the peptide composition and the second and third groupswith 500 and 5,000 micrograms of peptide composition, respectively. Thepatients within each group range in age from 21-65 and represent diverseethnic backgrounds. All of them have a tumor that expresses 98P4B6.

Clinical manifestations or antigen-specific T-cell responses aremonitored to assess the effects of administering the peptidecompositions. The vaccine composition is found to be both safe andefficacious in the treatment of 98P4B6-associated disease.

Example 31 Induction of CTL Responses Using a Prime Boost Protocol

A prime boost protocol similar in its underlying principle to that usedto confirm the efficacy of a DNA vaccine in transgenic mice, such asdescribed above in the Example entitled “The Plasmid Construct and theDegree to Which It Induces Immunogenicity,” can also be used for theadministration of the vaccine to humans. Such a vaccine regimen caninclude an initial administration of, for example, naked DNA followed bya boost using recombinant virus encoding the vaccine, or recombinantprotein/polypeptide or a peptide mixture administered in an adjuvant.

For example, the initial immunization may be performed using anexpression vector, such as that constructed in the Example entitled“Construction of “Minigene” Multi-Epitope DNA Plasmids” in the form ofnaked nucleic acid administered IM (or SC or ID) in the amounts of 0.5-5mg at multiple sites. The nucleic acid (0.1 to 1000 μg) can also beadministered using a gene gun. Following an incubation period of 3-4weeks, a booster dose is then administered. The booster can berecombinant fowlpox virus administered at a dose of 5-107 to 5×109 pfu.An alternative recombinant virus, such as an MVA, canarypox, adenovirus,or adeno-associated virus, can also be used for the booster, or thepolyepitopic protein or a mixture of the peptides can be administered.For evaluation of vaccine efficacy, patient blood samples are obtainedbefore immunization as well as at intervals following administration ofthe initial vaccine and booster doses of the vaccine. Peripheral bloodmononuclear cells are isolated from fresh heparinized blood byFicoll-Hypaque density gradient centrifugation, aliquoted in freezingmedia and stored frozen. Samples are assayed for CTL and HTL activity.

Analysis of the results indicates that a magnitude of responsesufficient to achieve a therapeutic or protective immunity against98P4B6 is generated.

Example 32 Administration of Vaccine Compositions Using Dendritic Cells(DC)

Vaccines comprising peptide epitopes of the invention can beadministered using APCs, or “professional” APCs such as DC. In thisexample, peptide-pulsed DC are administered to a patient to stimulate aCTL response in vivo. In this method, dendritic cells are isolated,expanded, and pulsed with a vaccine comprising peptide CTL and HTLepitopes of the invention. The dendritic cells are infused back into thepatient to elicit CTL and HTL responses in vivo. The induced CTL and HTLthen destroy or facilitate destruction, respectively, of the targetcells that bear the 98P4B6 protein from which the epitopes in thevaccine are derived.

For example, a cocktail of epitope-comprising peptides is administeredex vivo to PBMC, or isolated DC therefrom. A pharmaceutical tofacilitate harvesting of DC can be used, such as Progenipoietin™(Monsanto, St. Louis, Mo.) or GM-CSF/IL-4. After pulsing the DC withpeptides, and prior to reinfusion into patients, the DC are washed toremove unbound peptides.

As appreciated clinically, and readily determined by one of skill basedon clinical outcomes, the number of DC reinfused into the patient canvary (see, e.g., Nature Med. 4:328, 1998; Nature Med. 2:52, 1996 andProstate 32:272, 1997). Although 2-50×10 ⁶ DC per patient are typicallyadministered, larger number of DC, such as 10⁷ or 10⁸ can also beprovided. Such cell populations typically contain between 50-90% DC.

In some embodiments, peptide-loaded PBMC are injected into patientswithout purification of the DC. For example, PBMC generated aftertreatment with an agent such as Progenipoietin™ are injected intopatients without purification of the DC. The total number of PBMC thatare administered often ranges from 10⁸ to 10¹⁰. Generally, the celldoses injected into patients is based on the percentage of DC in theblood of each patient, as determined, for example, by immunofluorescenceanalysis with specific anti-DC antibodies. Thus, for example, ifProgenipoietin™ mobilizes 2% DC in the peripheral blood of a givenpatient, and that patient is to receive 5×10⁶ DC, then the patient willbe injected with a total of 2.5×10⁸ peptide-loaded PBMC. The percent DCmobilized by an agent such as Progenipoietin™ is typically estimated tobe between 2-10%, but can vary as appreciated by one of skill in theart.

Ex vivo activation of CTUHTL responses

Alternatively, ex vivo CTL or HTL responses to 98P4B6 antigens can beinduced by incubating, in tissue culture, the patient's, or geneticallycompatible, CTL or HTL precursor cells together with a source of APC,such as DC, and immunogenic peptides. After an appropriate incubationtime (typically about 7-28 days), in which the precursor cells areactivated and expanded into effector cells, the cells are infused intothe patient, where they will destroy (CTL) or facilitate destruction(HTL) of their specific target cells, i.e., tumor cells.

Example 33 An Alternative Method of Identifying and ConfirmingMotif-Bearing Peptides

Another method of identifying and confirming motif-bearing peptides isto elute them from cells bearing defined MHC molecules. For example, EBVtransformed B cell lines used for tissue typing have been extensivelycharacterized to determine which HLA molecules they express. In certaincases these cells express only a single type of HLA molecule. Thesecells can be transfected with nucleic acids that express the antigen ofinterest, e.g. 98P4B6. Peptides produced by endogenous antigenprocessing of peptides produced as a result of transfection will thenbind to HLA molecules within the cell and be transported and displayedon the cell's surface. Peptides are then eluted from the HLA moleculesby exposure to mild acid conditions and their amino acid sequencedetermined, e.g., by mass spectral analysis (e.g., Kubo et al., J.Immunol. 152:3913, 1994). Because the majority of peptides that bind aparticular HLA molecule are motif-bearing, this is an alternativemodality for obtaining the motif-bearing peptides correlated with theparticular HLA molecule expressed on the cell.

Alternatively, cell lines that do not express endogenous HLA moleculescan be transfected with an expression construct encoding a single HLAallele. These cells can then be used as described, i.e., they can thenbe transfected with nucleic acids that encode 98P4B6 to isolate peptidescorresponding to 98P4B6 that have been presented on the cell surface.Peptides obtained from such an analysis will bear motif(s) thatcorrespond to binding to the single HLA allele that is expressed in thecell.

As appreciated by one in the art, one can perform a similar analysis ona cell bearing more than one HLA allele and subsequently determinepeptides specific for each HLA allele expressed. Moreover, one of skillwould also recognize that means other than transfection, such as loadingwith a protein antigen, can be used to provide a source of antigen tothe cell.

Example 34 Complementary Polynucleotides

Sequences complementary to the 98P4B6-encoding sequences, or any partsthereof, are used to detect, decrease, or inhibit expression ofnaturally occurring 98P4B6. Although use of oligonucleotides comprisingfrom about 15 to 30 base pairs is described, essentially the sameprocedure is used with smaller or with larger sequence fragments.Appropriate oligonucleotides are designed using, e.g., OLIGO 4.06software (National Biosciences) and the coding sequence of 98P4B6. Toinhibit transcription, a complementary oligonucleotide is designed fromthe most unique 5′ sequence and used to prevent promoter binding to thecoding sequence. To inhibit translation, a complementary oligonucleotideis designed to prevent ribosomal binding to a 98P4B6-encodingtranscript.

Example 35 Purification of Naturally-Occurring or Recombinant 98P4B6Using 98P4B6-Specific Antibodies

Naturally occurring or recombinant 98P4B6 is substantially purified byimmunoaffinity chromatography using antibodies specific for 98P4B6. Animmunoaffinity column is constructed by covalently coupling anti-98P4B6antibody to an activated chromatographic resin, such as CNBr-activatedSEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the resin isblocked and washed according to the manufacturers instructions.

Media containing 98P4B6 are passed over the immunoaffinity column, andthe column is washed under conditions that allow the preferentialabsorbance of 98P4B6 (e.g., high ionic strength buffers in the presenceof detergent). The column is eluted under conditions that disruptantibody/98P4B6 binding (e.g., a buffer of pH 2 to pH 3, or a highconcentration of a chaotrope, such as urea or thiocyanate ion), andGCR.P is collected.

Example 36 Identification of Molecules Which Interact with 98P4B6

98P4B6, or biologically active fragments thereof, are labeled with 121 1Bolton-Hunter reagent. (See, e.g., Bolton et al. (1973) Biochem. J.133:529.) Candidate molecules previously arrayed in the wells of amulti-well plate are incubated with the labeled 98P4B6, washed, and anywells with labeled 98P4B6 complex are assayed. Data obtained usingdifferent concentrations of 98P4B6 are used to calculate values for thenumber, affinity, and association of 98P4B6 with the candidatemolecules.

Example 37 In Vivo Assay for 98P4B6 Tumor Growth Promotion

The effect of the 98P4B6 protein on tumor cell growth is evaluated invivo by gene overexpression in tumor-bearing mice. For example, prostate(PC3), lung (A427), stomach, ovarian (PAl) and uterus cell lines areengineered to express 98P4B6. SCID mice are injected subcutaneously oneach flank with 1×10⁶ of PC3, A427, PA1, or NIH-3T3 cells containingtkNeo empty vector or 98P4B6. At least two strategies may be used: (1)Constitutive 98P4B6 expression under regulation of a promoter such as aconstitutive promoter obtained from the genomes of viruses such aspolyoma virus, fowlpox virus (UK 2,211,504 published 5 Jul. 1989),adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcomavirus, cytomegalovirus, a retrovirus, hepatitis-B virus, and SimianVirus 40 (SV40), or from heterologous mammalian promoters, e.g., theactin promoter or an immunoglobulin promoter, provided such promotersare compatible with the host cell systems, and (2) Regulated expressionunder control of an inducible vector system, such as ecdysone, tet,etc., provided such promoters are compatible with the host cell systems.Tumor volume is then monitored at the appearance of palpable tumors andfollowed over time to determine if 98P4B6-expressing cells grow at afaster rate and whether tumors produced by 98P4B6-expressing cellsdemonstrate characteristics of altered aggressiveness (e.g. enhancedmetastasis, vascularization, reduced responsiveness to chemotherapeuticdrugs).

Additionally, mice can be implanted with 1×10⁵ of the same cellsorthotopically to determine if 98P4B6 has an effect on local growth inthe prostate or on the ability of the cells to metastasize, specificallyto lungs, lymph nodes, and bone marrow.

The assay is also useful to determine the 98P4B6 inhibitory effect ofcandidate therapeutic compositions, such as for example, 98P4B6intrabodies, 98P4B6 antisense molecules and ribozymes.

Example 38 98P4B6 Monoclonal Antibody-mediated Inhibition of Tumors InVivo.

The significant expression of 98P4B6 in prostate, lung, stomach, ovary,and uterus cancer tissues, its restrictive expression in normal tissues,together with its expected cell surface expression makes 98P4B6 anexcellent target for antibody therapy. Similarly, 98P4B6 is a target forT-cell based immunotherapy. Thus, the therapeutic efficacy ofanti-98P4B6 mAbs in human prostate cancer xenograft mouse models isevaluated by using androgen-independent LAPC-4 and LAPC-9 xenografts(Craft, N., et al., Cancer Res, 1999. 59(19): p. 5030-6) and theandrogen independent recombinant cell line PC3-98P4B6 (see, e.g.,Kaighn, M. E., et al., Invest Urol, 1979. 17(1): p. 16-23). Similarapproaches using patient derived xenografts or xenograft cell lines areused for cancers listed in Table I.

Antibody efficacy on tumor growth and metastasis formation is studied,e.g., in a mouse orthotopic prostate cancer xenograft models and mouselung, uterus, or stomach xenograft models. The antibodies can beunconjugated, as discussed in this Example, or can be conjugated to atherapeutic modality, as appreciated in the art. Anti-98P4B6 mAbsinhibit formation of both the androgen-dependent LAPC-9 andandrogen-independent PC3-98P4B6 tumor xenografts. Anti-98P4B6 mAbs alsoretard the growth of established orthotopic tumors and prolongedsurvival of tumor-bearing mice. These results indicate the utility ofanti-98P4B6 mAbs in the treatment of local and advanced stages ofcancer. (See, e.g., (Saffran, D., et al., PNAS 10:1073-1078).

Administration of the anti-98P4B6 mAbs can lead to retardation ofestablished orthotopic tumor growth and inhibition of metastasis todistant sites, resulting in a significant prolongation in the survivalof tumor-bearing mice. These studies indicate that 98P4B6 is anattractive target for immunotherapy and demonstrate the therapeuticpotential of anti-98P4B6 mAbs for the treatment of local and metastaticcancer. This example demonstrates that unconjugated 98P4B6 monoclonalantibodies are effective to inhibit the growth of human prostate tumorxenografts, as well as lung, uterus, or stomach xenograft grown in SCIDmice; accordingly a combination of such efficacious monoclonalantibodies is also effective.

Tumor Inhibition Using Multiple Unconjugated 98P4B6 mAbs

Materials and Methods

98P4B6 Monoclonal Antibodies:

Monoclonal antibodies are raised against 98P4B6 as described in Example11 entitled “Generation of 98P4B6 Monoclonal Antibodies (mAbs).” Theantibodies are characterized by ELISA, Western blot, FACS, andimmunoprecipitation for their capacity to bind 98P4B6. Epitope mappingdata for the anti-98P4B6 mAbs, as determined by ELISA and Westernanalysis, recognize epitopes on the 98P4B6 protein. Immunohistochemicalanalysis of cancer tissues and cells with these antibodies is performed.

The monoclonal antibodies are purified from ascites or hybridoma tissueculture supernatants by Protein-G Sepharose chromatography, dialyzedagainst PBS, filter sterilized, and stored at −20° C. Proteindeterminations are performed by a Bradford assay (Bio-Rad, Hercules,Calif.). A therapeutic monoclonal antibody or a cocktail comprising amixture of individual monoclonal antibodies is prepared and used for thetreatment of mice receiving subcutaneous or orthotopic injections ofLAPC-9 tumor xenografts.

Cancer Xenografts and Cell Lines

The LAPC-9 xenograft, which expresses a wild-type androgen receptor andproduces prostate-specific antigen (PSA), is passaged in 6- to8-week-old male ICR-severe combined immunodeficient (SCID) mice (TaconicFarms) by s.c. trocar implant (Craft, N., et al., supra). The prostate(PC3), lung (A427), ovarian (PA1) carcinoma cell lines (American TypeCulture Collection) are maintained in RPMI or DMEM supplemented withL-glutamine and 10% FBS.

PC3-98P4B6, A427-98P4B6, PA1-98P4B6 and 3T3-98P4B6 cell populations aregenerated by retroviral gene transfer as described in Hubert, R. S., etal., STEAP: a prostate-specific cell-surface antigen highly expressed inhuman prostate tumors. Proc Nat Acad Sci USA, 1999. 96(25): p. 14523-8.Anti-98P4B6 staining is detected by using an FITC-conjugated goatanti-mouse antibody (Southern Biotechnology Associates) followed byanalysis on a Coulter Epics-XL flow cytometer.

Xenograft Mouse Models.

Subcutaneous (s.c.) tumors are generated by injection of 1×10⁶ LAPC-9,PC3, PC3-98P4B6, A427, A427-98P4B6, PA1, PA1-98P4B6, 3T3 or 3T3-98P4B6cells mixed at a 1:1 dilution with Matrigel (Collaborative Research) inthe right flank of male SCID mice. To test antibody efficacy on tumorformation, i.p. antibody injections are started on the same day astumor-cell injections. As a control, mice are injected with eitherpurified mouse IgG (ICN) or PBS; or a purified monoclonal antibody thatrecognizes an irrelevant antigen not expressed in human cells. Inpreliminary studies, no difference is found between mouse IgG or PBS ontumor growth. Tumor sizes are determined by vernier calipermeasurements, and the tumor volume is calculated as length x width xheight. Mice with s.c. tumors greater than 1.5 cm in diameter aresacrificed. PSA levels are determined by using a PSA ELISA kit (Anogen,Mississauga, Ontario). Circulating levels of anti-98P4B6 mAbs aredetermined by a capture ELISA kit (Bethyl Laboratories, Montgomery,Tex.). (See, e.g., (Saffran, D., et al., PNAS 10:1073-1078).

Orthotopic injections are performed under anesthesia by usingketamine/xylazine. For prostate orthotopic studies, an incision is madethrough the abdominal muscles to expose the bladder and seminalvesicles, which then are delivered through the incision to expose thedorsal prostate. LAPC-9 or PC3 cells (5×10⁵ ) mixed with Matrigel areinjected into each dorsal lobe in a 10μl volume. To monitor tumorgrowth, mice are bled on a weekly basis for determination of PSA levels.The mice are segregated into groups for the appropriate treatments, withanti-98P4B6 or control mAbs being injected i.p.

Anti-98P4B6 mAbs Inhibit Growth of 98P4B6-Expressing Xenograft-CancerTumors

The effect of anti-98P4B6 mAbs on tumor formation is tested by usingLAPC-9 and PC3-98P4B6 orthotopic models. As compared with the s.c. tumormodel, the orthotopic model, which requires injection of tumor cellsdirectly in the mouse prostate, lung, or ovary, respectively, results ina local tumor growth, development of metastasis in distal sites,deterioration of mouse health, and subsequent death (Saffran, D., etal., PNAS supra; Fu, X., et al., Int J Cancer, 1992. 52(6): p. 987-90;Kubota, T., J Cell Biochem, 1994. 56(1): p. 4-8). The features make theorthotopic model more representative of human disease progression andallowed us to follow the therapeutic effect of mAbs on clinicallyrelevant end points.

Accordingly, tumor cells are injected into the mouse prostate, lung, orovary, and 2 days later, the mice are segregated into two groups andtreated with either: a) 200-500μg, of anti-98P4B6 Ab, or b) PBS threetimes per week for two to five weeks.

A major advantage of the orthotopic cancer model is the ability to studythe development of metastases. Formation of metastasis in mice bearingestablished orthotopic tumors is studies by IHC analysis on lungsections using an antibody against a prostate-specific cell-surfaceprotein STEAP expressed at high levels in LAPC-9 xenografts (Hubert, R.S., et al., Proc Natl Acad Sci USA, 1999. 96(25): p. 14523-8).

Mice bearing established orthotopic LAPC-9 or PC3-98P4B6 tumors areadministered 1000 μg injections of either anti-98P4B6 mAb or PBS over a4-week period. Mice in both groups are allowed to establish a high tumorburden (PSA levels greater than 300 ng/ml for IAPC-9), to ensure a highfrequency of metastasis formation in mouse lungs. Mice then are killedand their prostate and lungs are analyzed for the presence of tumorcells by IHC analysis.

These studies demonstrate a broad anti-tumor efficacy of anti-98P4B6antibodies on initiation and progression of prostate cancer in xenograftmouse models. Anti-98P4B6 antibodies inhibit tumor formation of bothandrogen-dependent and androgen-independent tumors as well as retardingthe growth of already established tumors and prolong the survival oftreated mice. Moreover, anti-98P4B6 mAbs demonstrate a dramaticinhibitory effect on the spread of local prostate tumor to distal sites,even in the presence of a large tumor burden. Thus, anti-98P4B6 mAbs areefficacious on major clinically relevant end points (tumor growth),prolongation of survival, and health.

Example 39 Therapeutic and Diagnostic Use of Anti-98P4B6 Antibodies inHumans.

Anti-98P4B6 monoclonal antibodies are safely and effectively used fordiagnostic, prophylactic, prognostic and/or therapeutic purposes inhumans. Western blot and immunohistochemical analysis of cancer tissuesand cancer xenografts with anti-98P4B6 mAb show strong extensivestaining in carcinoma but significantly lower or undetectable levels innormal tissues. Detection of 98P4B6 in carcinoma and in metastaticdisease demonstrates the usefulness of the mAb as a diagnostic and/orprognostic indicator. Anti-98P4B6 antibodies are therefore used indiagnostic applications such as immunohistochemistry of kidney biopsyspecimens to detect cancer from suspect patients.

As determined by flow cytometry, anti-98P4B6 mAb specifically binds tocarcinoma cells. Thus, anti-98P4B6 antibodies are used in diagnosticwhole body imaging applications, such as radioimmunoscintigraphy andradioimmunotherapy, (see, e.g., Potamianos S., et. al. Anticancer Res20(2A):925-948 (2000)) for the detection of localized and metastaticcancers that exhibit expression of 98P4B6. Shedding or release of anextracellular domain of 98P4B6 into the extracellular milieu, such asthat seen for alkaline phosphodiesterase B10 (Meerson, N. R., Hepatology27:563-568 (1998)), allows diagnostic detection of 98P4B6 by anti-98P4B6antibodies in serum and/or urine samples from suspect patients.

Anti-98P4B6 antibodies that specifically bind 98P4B6 are used intherapeutic applications for the treatment of cancers that express98P4B6. Anti-98P4B6 antibodies are used as an unconjugated modality andas conjugated form in which the antibodies are attached to one ofvarious therapeutic or imaging modalities well known in the art, such asa prodrugs, enzymes or radioisotopes. In preclinical studies,unconjugated and conjugated anti-98P4B6 antibodies are tested forefficacy of tumor prevention and growth inhibition in the SCID mousecancer xenograft models, e.g., kidney cancer models AGS-K3 and AGS-K6,(see, e.g., the Example entitled “98P4B6 Monoclonal Antbody-mediatedInhibition of Bladder and Lung Tumors In Vivo”. Either conjugated andunconjugated anti-98P4B6 antibodies are used as a therapeutic modalityin human clinical trials either alone or in combination with othertreatments as described in following Examples.

Example 40 Human Clinical Trials for the Treatment and Diagnosis ofHuman Carcinomas through use of Human Anti-98P4B6 Antibodies In vivo

Antibodies are used in accordance with the present invention whichrecognize an epitope on 98P4B6, and are used in the treatment of certaintumors such as those listed in Table I. Based upon a number of factors,including 98P4B6 expression levels, tumors such as those listed in TableI are presently preferred indications. In connection with each of theseindications, three clinical approaches are successfully pursued.

I.) Adjunctive therapy: In adjunctive therapy, patients are treated withanti-98P4B6 antibodies in combination with a chemotherapeutic orantineoplastic agent and/or radiation therapy. Primary cancer targets,such as those listed in Table I, are treated under standard protocols bythe addition anti-98P4B6 antibodies to standard first and second linetherapy. Protocol designs address effectiveness as assessed by reductionin tumor mass as well as the ability to reduce usual doses of standardchemotherapy. These dosage reductions allow additional and/or prolongedtherapy by reducing dose-related toxicity of the chemotherapeutic agent.Anti-98P4B6 antibodies are utilized in several adjunctive clinicaltrials in combination with the chemotherapeutic or antineoplastic agentsadriamycin (advanced prostrate carcinoma), cisplatin (advanced head andneck and lung carcinomas), taxol (breast cancer), and doxorubicin(preclinical).

II.) Monotherapy: In connection with the use of the anti-98P4B6antibodies in monotherapy of tumors, the antibodies are administered topatients without a chemotherapeutic or antineoplastic agent. In oneembodiment, monotherapy is conducted clinically in end stage cancerpatients with extensive metastatic disease. Patients show some diseasestabilization. Trials demonstrate an effect in refractory patients withcancerous tumors.

III.) Imaging Agent: Through binding a radionuclide (e.g., iodine oryttrium (I¹³¹, Y⁹⁰) to anti-98P4B6 antibodies, the radiolabeledantibodies are utilized as a diagnostic and/or imaging agent. In such arole, the labeled antibodies localize to both solid tumors, as well as,metastatic lesions of cells expressing 98P4B6. In connection with theuse of the anti-98P4B6 antibodies as imaging agents, the antibodies areused as an adjunct to surgical treatment of solid tumors, as both apre-surgical screen as well as a post-operative follow-up to determinewhat tumor remains and/or returns. In one embodiment, a (¹¹¹In)-98P4B6antibody is used as an imaging agent in a Phase I human clinical trialin patients having a carcinoma that expresses 98P4B6 (by analogy see,e.g., Divgi et al. J. Natl. Cancer Inst 83:97-104 (1991)). Patients arefollowed with standard anterior and posterior gamma camera. The resultsindicate that primary lesions and metastatic lesions are identified

Dose and Route of Administration

As appreciated by those of ordinary skill in the art, dosingconsiderations can be determined through comparison with the analogousproducts that are in the clinic. Thus, anti-98P4B6 antibodies can beadministered with doses in the range of 5 to 400 mg/m², with the lowerdoses used, e.g., in connection with safety studies. The affinity ofanti-98P4B6 antibodies relative to the affinity of a known antibody forits target is one parameter used by those of skill in the art fordetermining analogous dose regimens. Further, anti-98P4B6 antibodiesthat are fully human antibodies, as compared to the chimeric antibody,have slower clearance; accordingly, dosing in patients with such fullyhuman anti-98P4B6 antibodies can be lower, perhaps in the range of 50 to300 mg/m², and still remain efficacious. Dosing in mg/m², as opposed tothe conventional measurement of dose in mg/kg, is a measurement based onsurface area and is a convenient dosing measurement that is designed toinclude patients of all sizes from infants to adults.

Three distinct delivery approaches are useful for delivery ofanti-98P4B6 antibodies. Conventional intravenous delivery is onestandard delivery technique for many tumors. However, in connection withtumors in the peritoneal cavity, such as tumors of the ovaries, biliaryduct, other ducts, and the like, intraperitoneal administration mayprove favorable for obtaining high dose of antibody at the tumor and toalso minimize antibody clearance. In a similar manner, certain solidtumors possess vasculature that is appropriate for regional perfusion.Regional perfusion allows for a high dose of antibody at the site of atumor and minimizes short term clearance of the antibody.

Clinical Development Plan (CDP)

Overview: The CDP follows and develops treatments of anti-98P4B6antibodies in connection with adjunctive therapy, monotherapy, and as animaging agent. Trials initially demonstrate safety and thereafterconfirm efficacy in repeat doses. Trails are open label comparingstandard chemotherapy with standard therapy plus anti-98P4B6 antibodies.As will be appreciated, one criteria that can be utilized in connectionwith enrollment of patients is 98P4B6 expression levels in their tumorsas determined by biopsy.

As with any protein or antibody infusion-based therapeutic, safetyconcerns are related primarily to (i) cytokine release syndrome, i.e.,hypotension, fever, shaking, chills; (ii) the development of animmunogenic response to the material (i.e., development of humanantibodies by the patient to the antibody therapeutic, or HAHAresponse); and, (iii) toxicity to normal cells that express 98P4B6.Standard tests and follow-up are utilized to monitor each of thesesafety concerns. Anti-98P4B6 antibodies are found to be safe upon humanadministration.

Example 41 Human Clinical Trial Adjunctive Therapy with HumanAnti-98P4B6 Antibody and Chemotherapeutic Agent

A phase I human clinical trial is initiated to assess the safety of sixintravenous doses of a human anti-98P4B6 antibody in connection with thetreatment of a solid tumor, e.g., a cancer of a tissue listed in TableI. In the study, the safety of single doses of anti-98P4B6 antibodieswhen utilized as an adjunctive therapy to an antineoplastic orchemotherapeutic agent as defined herein, such as, without limitation:cisplatin, topotecan, doxorubicin, adriamycin, taxol, or the like, isassessed. The trial design includes delivery of six single doses of ananti-98P4B6 antibody with dosage of antibody escalating fromapproximately about 25 mg/m² to about 275 mg/m² over the course of thetreatment in accordance with the following schedule:

Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 mAb Dose 25 75 125 175 225 275mg/m² mg/m² mg/m² mg/m² mg/m² mg/m² Chemotherapy + + + + + + (standarddose)

Patients are closely followed for one-week following each administrationof antibody and chemotherapy. In particular, patients are assessed forthe safety concerns mentioned above: (i) cytokine release syndrome,i.e., hypotension, fever, shaking, chills; (ii) the development of animmunogenic response to the material (i.e., development of humanantibodies by the patient to the human antibody therapeutic, or HAHAresponse); and, (iii) toxicity to normal cells that express 98P4B6.Standard tests and follow-up are utilized to monitor each of thesesafety concerns. Patients are also assessed for clinical outcome, andparticularly reduction in tumor mass as evidenced by MRI or otherimaging.

The anti-98P4B6 antibodies are demonstrated to be safe and efficacious,Phase II trials confirm the efficacy and refine optimum dosing.

Example 42 Human Clinical Trial: Monotherapy with Human Anti-98P4B6Antibody

Anti-98P4B6 antibodies are safe in connection with the above-discussedadjunctive trial, a Phase II human clinical trial confirms the efficacyand optimum dosing for monotherapy. Such trial is accomplished, andentails the same safety and outcome analyses, to the above-describedadjunctive trial with the exception being that patients do not receivechemotherapy concurrently with the receipt of doses of anti-98P4B6antibodies.

Example 43 Human Clinical Trial: Diagnostic Imaging with Anti-98P4B6Antibody

Once again, as the adjunctive therapy discussed above is safe within thesafety criteria discussed above, a human clinical trial is conductedconcerning the use of anti-98P4B6 antibodies as a diagnostic imagingagent. The protocol is designed in a substantially similar manner tothose described in the art, such as in Divgi et al. J. Natl. CancerInst. 83:97-104 (1991). The antibodies are found to be both safe andefficacious when used as a diagnostic modality.

Example 44 Homology Comparison of 98P4B6 to Known Sequences

The 98P4B6 gene is homologous to a cloned and sequenced gene, namelyhuman STAMP1 (gi 15418732) (Korkmaz, K. S et al, J. Biol. Chem. 2002,277: 36689), showing 99% identity and 99% homology to that gene (FIG.4). The 98P4B6 protein also shows 99% identity and 99% homology toanother human six transmembrane epithelial antigen of prostate 2 (gi23308593) (Walker, M. G et al, Genome Res. 1999, 9:1198; Porkka, K. P.,Helenius, M. A. and Visakorpi, T, Lab. Invest. 2002, 82: 1573). Theclosest mouse homolog to 98P4B6is six transmembrane epithelial antigenof prostate 2 (gi 28501136), with 97% identity and 99% homology. We haveidentified several variants of the 98P4B6 protein, including 4 splicevariants and 3 SNPs (FIG. 11). The 98P4B6 v.1 protein consists of 454amino acids, with calculated molecular weight of 52kDa, and pl of 8.7.It is a 6 transmembrane protein that can localize to the cell surface orpossibly to the endoplasmic reticulum (Table VI). Several 98P4B6variants, including v.1, v.5-8, v.13, v.14, v.21, v.25 share similarfeatures, such protein motifs with functional significance, as well asstructural commonalities such as multiple transmembrane domains. The98P4B6 v.2 is a short protein with no known motifs.

Motif analysis revealed the presence of several known motifs, includingoxido-reductase, homocysteine hydrolase and dudulin motifs. Variant v.7and SNPs of this variant also carry an Ets motif, often associated withtranscriptional activity.

Several oxidoreductases have been identified in mammalian cells,including the NADH/quinone oxidoreductase. This protein associate withthe cell membrane and function as a proton/Na+ pump, which regulates theprotein degradation of the tumor suppressor p53, and protects mammaliancells from oxidative stress, cytotoxicity, and mutages (Asher G, et al,Proc Natl Acad Sci USA. 2002, 99:13125; Jaiswal A K, Arch BiochemBiophys 2000, 375:62 Yano T, Mol Aspects Med 2002, 23:345). Homocysteinehydrolase is an enzyme known to catalyze the breakdown ofS-adenosylhomocysteine to homocysteine and adenosine, ultimatelyregulating trans-methylation, therby regulating protein expression, cellcycle and proliferation (Turner M A et al. Cell Biochem Biophys2000;33:101; Zhang et al, J Biol Chem. 2001; 276:35867)

This information indicates that 98P4B6 plays a role in the cell growthof mammalian cells, regulate gene transcription and transport ofelectrons and small molecules. Accordingly, when 98P4B6 functions as aregulator of cell growth, tumor formation, or as a modulator oftranscription involved in activating genes associated with inflammation,tumorigenesis, or proliferation, 98P4B6 is used for therapeutic,diagnostic, prognostic and/or preventative purposes. In addition, when amolecule, such as a variant or polymorphism of 98P4B6 is expressed incancerous tissues, it is used for therapeutic, diagnostic, prognosticand/or preventative purposes.

Example 45 Phenotypic Effects of STEAP-2 Expression

Experiments regarding the expression of STEAP-2 protein having the aminoacid sequence shown in FIG. 2 and encoded by a cDNA insert in a plasmiddeposited with the American Type Culture Collection on 2 Jul. 1999 andassigned as ATCC Accession No. PTA-311. As deduced from the codingsequence, the open reading frame encodes 454 amino acids with 6transmembrane domains. A summary of the characteristics associated withSTEAP-2 protein is shown on FIG. 19.

This deposit was made under the provisions of the Budapest Treaty on theInternational Recognition of the Deposit of Microorganisms for thePurpose of Patent Procedure and the Regulations thereunder (BudapestTreaty). This assures maintenance of a viable culture of the deposit for30 years from the date of deposit and for at least five (5) years afterthe most recent request for the furnishing of a sample of the depositreceived by the depository. The deposits will be made available by ATCCunder the terms of the Budapest Treaty, and subject to an agreementbetween Genentech, Inc. and ATCC, which assures that all restrictionsimposed by the depositor on the availability to the public of thedeposited material will be irrevocably removed upon the granting of thepertinent U.S. patent, assures permanent and unrestricted availabilityof the progeny of the culture of the deposit to the public upon issuanceof the pertinent U.S. patent or upon laying open to the public of anyU.S. or foreign patent application, whichever comes first, and assuresavailability of the progeny to one determined by the U.S. Commissionerof Patents and Trademarks to be entitled thereto according to 35 USC §122 and the Commissioner's rules pursuant thereto (including 37 CFR §1.14 with particular reference to 886 OG 638).

The assignee of the present application has agreed that if a culture ofthe materials on deposit should die or be lost or destroyed whencultivated under suitable conditions, the materials will be promptlyreplaced on notification with another of the same. Availability of thedeposited material is not to be construed as a license to practice theinvention in contravention of the rights granted under the authority ofany government in accordance with its patent laws.

The data set forth in the present patent application provide anexpression profile of the STEAP-2 protein that is predominantly specificfor the prostate among normal tissues, for certain types of prostatetumors as well as other tumors. This evidence is based on detectingmessenger RNA using Northern blotting. In keeping with standard practicein this industry, Northern blots are routinely used to assess geneexpression, as it does not require the time consuming process ofsynthesizing the relevant protein, raising antibodies, assuring thespecificity of the antibodies, required for Western blotting of proteinsand the histological examination of tissues. Northern blotting offers acredible and efficient method of assessing RNA expression and expressionlevels.

This Example demonstrates that STEAP-2 protein is, indeed, produced. Insummary, the experiments show that PC-3 cells and 3T3 cells which weremodified to contain an expression system for STEAP-2 showed enhancedlevels of tyrosine phosphorylation in general, and of phosphorylation ofERK protein in particular. The data also show that PC-3 cells thatcontain an expression system for STEAP-2 showed modified calcium flux, amodified response to paclitaxel, and a general inhibition ofdrug-induced apoptosis. These are effects exhibited at the proteinlevel, thus these data alone are probative that the STEAP-2 proteinexists.

Furthermore, although such phenotypic effects are protein-mediated,further evidence indicates that the STEAP-2 protein itself is themediator of the effects. This evidence is obtained by utilizing amodified STEAP-2 protein. An expression system is stably introduced intoPC3 and 3T3 cells which allows the expression of a modified form ofSTEAP-2, designated STEAP-2CFl, where “Fl” stands for flag. STEAP-2CFlis a STEAP-2 protein having a peptide extension, i.e., a Flag epitopethat alters the physical conformation of this protein. The Flag epitopeis a string 8 amino acids, often introduced at either the amino orcarboxy termini of protein as a means of identifying and following arecombinant protein in engineered cells (Slootstra J W et al, Mol Divers1997, 2:156). In most cases, the introduction of the Flag epitope ateither termini of a protein has little effect on the natural functionand location of that protein (Molloy SS et al, EMBO J 1994, 13:18).However, this is dependent on the characteristics of the protein beingFlag tagged. Recent studies have shown that a Flag tag affects thefunction and conformation of select proteins such as the CLN3 protein(see, e.g., Haskell R E, et al. Mol Genet Metab 1999, 66:253). As withCLN3, introducing a Flag epitope tag to the C-terminus of STEAP-2 altersthe physical conformation and properties of this protein. Altering theSTEAP-2 protein with the C-Flag epitope resulted in a significantdecrease in the effects otherwise observed, including phosphorylation ofERK and resistance to drug-induced cell death. The data indicate that itis the STEAP-2 protein that mediated these phenotypic effects. Finally,in vitro translation studies using rabbit reticulocyte lysate, showedthat the STEAP-2 protein is translated and exhibits the expectedmolecular weight.

FIGS. 20 and 21 show the results obtained when PC-3 and 3T3 cells,respectively, were modified to contain the retroviral expression systempSRO encoding the indicated proteins, including STEAP-1, STEAP-2 andSTEAP-2CFl, respectively. Gene-specific protein expression was drivenfrom a long terminal repeat (LTR), and the Neomycin resistance gene wasused for selection of mammalian cells that stably express the protein.PC-3 and 3T3 cells were transduced with the retrovirus, selected in thepresence of G418 and cultured under conditions which permit expressionof the STEAP-2 coding sequence. The cells were grown overnight in lowconcentrations of FBS (0.5-1% FBS) and were then stimulated with 10%FBS. The cells were lysed in RIPA buffer and quantitated for proteinconcentration. Whole cell lysates were separated by SDS-PAGE andanalyzed by Western blotting using anti-phospho-ERK (Cell SignalingInc.) or anti-phosphotyrosine (UBI) antibodies (FIGS. 20, 21, and 22).As shown on FIG. 20, as compared to untransformed PC-3 cells, cellsmodified to contain STEAP-2 contain enhanced amounts of phosphorylatedtyrosine. Similar results from an analogous experiment on 3T3 cells areshown on page 3. In this latter experiment, the STEAP-2CFl expressionsystem was also transfected into 3T3 cells, which cells were used as acontrol. As shown on FIG. 21, the enhanced phosphorylation found in thepresence of native STEAP-2 was significantly reduced when theconformation of the protein was altered. These results thus showconclusively that the STEAP-2 protein was produced and mediated theabove-described phenotypic effects.

FIG. 22 shows similar results, both in PC-3 and 3T3 cells wherephosphorylation of ERK, specifically, is detected. The protocol issimilar to that set forth in paragraph 5 above, except that rather thanprobing the gels with antibodies specific for phosphotyrosine the gelswere probed both the anti-ERK and anti-phospho-ERK antibodies. As shownon FIG. 22, in the presence of 10% FBS, both PC-3 cells and 3T3 cellsmodified to express STEAP-2 showed phosphorylation of ERK which was notdetectable in cells transformed to contain STEAP-2CFl. In contrast tocontrol PC-3 cells which exhibit no background ERK phosphorylation,control 3T3-neo cells show low levels of endogenous ERK phosphorylation.Treatment with 10% FBS enhanced phosphorylation of ERK protein in cellsexpressing STEAP-2 relative to 3T3-neo cells, while no increase in ERKphosphorylation was observed in 3T3 cells expressing modified STEAP-2,i.e. STEAP-2 CFl.

Other effects on cellular metabolism in cells modified to contain aSTEAP-2 expression system were also shown in our data. FIG. 23 showsthat when cells with and without expression systems for STEAP-2 weremeasured for calcium flux in the presence of LPA, calcium flux wasenhanced in the STEAP-2 containing cells. Using FACS analysis andcommercially available indicators (Molecular Probes), parental cells andcells expressing STEAP-2 were compared for their ability to transportcalcium. PC3-neo and PC3-STEAP-2 cells were loaded with calciumresponsive indicators Fluo4 and Fura red, incubated in the presence orabsence of calcium and LPA, and analyzed by flow cytometry. PC3 cellsexpressing a known calcium transporter, PC3-83P3H3 pCaT were used aspositive control (Biochem Biophys Res Commun. 2001, 282:729). The tableon FIG. 23 shows that STEAP-2 mediates calcium flux in response to LPA,and that the magnitude of calcium flux is comparable to that produced bya known calcium channel.

In addition, STEAP-2 expressing PC3 cells demonstrated increasedsensitivity to agatoxin, a calcium channel blocker as compared toPC3-neo cells. These results indicate that STEAP-2 expression rendersPC3 cells sensitive to treatment with the Ca++ channel inhibitors.Information derived from the above experiments provides a mechanism bywhich cancer cells are regulated. This is particularly relevant in thecase of calcium, as calcium channel inhibitors have been reported toinduce the death of certain cancer cells, including prostate cancer celllines (see, e.g., Batra S, Popper LD, Hartley-Asp B. Prostate.1991,19:299).

FIG. 24 shows that cells transfected with a STEAP-2 expression systemhave enhanced ability to survive exposure to paclitaxel. In order todetermine the effect of STEAP-2 on survival, PC3 cells lacking orexpressing STEAP-2 were treated with chemotherapeutic agents currentlyused in the clinic. Effect of treatment was evaluated by measuring cellproliferation using the Alamare blue assay (FIG. 23). While only 5.2% ofPC3-neo cells were able to metabolize Alalmare Blue and proliferate inthe presence of 5 μM paclitaxel, 44.8% of PC3-STEAP-2 cells survivedunder the same conditions. These results indicate that expression ofSTEAP-2 imparts resistance to paclitaxel. These findings havesignificant in vivo implications, as they indicate that STEAP-2 providesa growth advantage for prostate tumor cells in patients treated withcommon therapeutic agents.

A more detailed form of these results is shown on FIGS. 25 and 26.Results in these two pages demonstrate the mode of action by whichSTEAP-2 supports the survival of PC3 cells. In these studies, PC3 cellsexpressing or lacking STEAP-2 were treated with paclitaxel for 60 hours,and assayed for apoptosis using annexin V conjugated to FITC andpropidium iodide staining. In apoptotic cells, the membrane phospholipidphosphatidylserine (PS) is translocated from the inner to the outerleaflet of the membrane, thereby exposing PS to the external cellularenvironment. PS is recognized by and binds to annexin V, providingscientists with a reliable means of identifying cells undergoingprogrammed cell death. Staining with propidium iodide identifies deadcells. FIG. 25 show that expression of STEAP-2 inhibitspaclitaxel-mediated apoptosis by 45% relative to paclitaxel-treatedPC3-neo cells. The protective effect of STEAP-2 is inhibited whenSTEAP-2 is modified by the presence of Flag at its C-terminus FIG. 26.

The publicly available literature contains several examples of prostateand other cancers that exhibit similar phenotypic characteristics asthose observed in PC3 cells that express STEAP-2. In particular,clinical studies have reported transient tumor regression and/or onlypartial responses in patents treated with paclitaxel. For instance, onlyaround 50% of prostate cancer patients entered in a single agentclinical trial of paclitaxel showed reduced PSA levels when treated withdoses of paclitaxel that induced grade 3 and grade 4 toxicity; a muchhigher level of response would have been expected based on this doselevel, thus this data indicates the development of paclitaxel resistancein prostate cancer patients (Beer T M et al, Ann Oncol 2001, 12:1273). Asimilar phenomenon of reduced responsiveness and progressive tumorrecurrence was observed in other studies (see, e.g., Obasaju C, andHudes G R. Hematol Oncol Clin North Am 2001, 15:525). In addition,inhibition of calcium flux in cells that endogenously express STEAP-2,such as LNCaP cells, induces their cell death (Skryma R et al, JPhysiol. 2000, 527:71).

Thus, STEAP-2 protein is produced not only in the cells tested, but alsoin unmodified tumor cells or unmodified prostate cells where thepresence of mRNA has been shown. The Northern blot data in thespecification clearly show that the messenger RNA encoding STEAP-2 isproduced in certain prostate and tumor cells. The 3T3 and PC-3 cells,which are themselves tumor cell lines, are clearly able to translate themessenger RNA into protein. Because it has been shown that there is nobarrier to translation of the message in cells similar to those tumorand prostate cells in which the mRNA has been shown to be produced, itcan properly be concluded that the protein itself can be detected in theunmodified tumor or prostate cells, given the fact that it is shown thatmRNA is produced. This conclusion is also supported by the patterns ofphenotypic changes seen in cells specifically modified to expressSTEAP-2, these changes comport with changes seen in cancer cells. Basedon the above data, it is scientifically concluded that cells and tissueswhich produce mRNA encoding STEAP-2 also produce the protein itself.

Example 46 Identification and Confirmation of Potential SignalTransduction Pathways

Many mammalian proteins have been reported to interact with signalingmolecules and to participate in regulating signaling pathways (JNeurochem. 2001; 76:217-223. Using immunoprecipitation and Westernblotting techniques, proteins are identified that associate with 98P4B6and mediate signaling events. Several pathways known to play a role incancer biology can be regulated by 98P4B6, including phospholipidpathways such as P13K, AKT, etc, adhesion and migration pathways,including FAK, Rho, Rac-1, etc, as well as mitogenic/survival cascadessuch as ERK, p38, etc (Cell Growth Differ. 2000,11:279; J Biol Chem.1999, 274:801; Oncogene. 2000,19:3003, J. Cell Biol. 1997,138:913.).

To confirm that 98P4B6 directly or indirectly activates known signaltransduction pathways in cells, luciferase (luc) based transcriptionalreporter assays are carried out in cells expressing individual genes.These transcriptional reporters contain consensus-binding sites forknown transcription factors that lie downstream of well-characterizedsignal transduction pathways. The reporters and examples of theseassociated transcription factors, signal transduction pathways, andactivation stimuli are listed below.

-   -   1. NFkB-luc, NFkB/Rel; Ik-kinase/SAPK; growth/apoptosis/stress    -   2. SRE-luc, SRF/TCF/ELK1; MAPK/SAPK; growth/differentiation    -   3. AP-1-luc, FOS/JUN; MAPK/SAPK/PKC; growth/apoptosis/stress    -   4. ARE-luc, androgen receptor; steroids/MAPK;        growth/differentiation/apoptosis    -   5. p53-luc, p53; SAPK; growth/differentiation/apoptosis    -   6. CRE-luc, CREB/ATF2; PKA/p38; growth/apoptosis/stress

Gene-mediated effects can be assayed in cells showing mRNA expression.Luciferase reporter plasmids can be introduced by lipid-mediatedtransfection (TFX-50, Promega). Luciferase activity, an indicator ofrelative transcriptional activity, is measured by incubation of cellextracts with luciferin substrate and luminescence of the reaction ismonitored in a luminometer.

Signaling pathways activated by 98P4B6 are mapped and used for theidentification and validation of therapeutic targets. When 98P4B6 isinvolved in cell signaling, it is used as target for diagnostic,prognostic, preventative and/or therapeutic purposes.

Example 47 98P4B6 Functions as a Proton or Small Molecule Transporter

Sequence and homology analysis of 98P4B6 indicate that the 98P4B6 mayfunction as a transporter. To confirm that STEAP-1 functions as an ionchannel, FACS analysis and fluorescent microscopy techniques are used(Gergely L, et al., Clin Diagn Lab Immunol. 1997; 4:70; Skryma R, etal., J Physiol. 2000, 527: 71). Using FACS analysis and commerciallyavailable indicators (Molecular Probes), parental cells and cellsexpressing 98P4B6 are compared for their ability to transport electrons,sodium, calcium; as well as other small molecules in cancer and normalcell lines. For example, PC3 and PC3-98P4B6 cells were loaded withcalcium responsive indicators Fluo4 and Fura red, incubated in thepresence or absence of calcium and lipophosphatidic acid (LPA), andanalyzed by flow cytometry. Ion flux represents an important mechanismby which cancer cells are regulated. This is particularly true in thecase of calcium, as calcium channel inhibitors have been reported toinduce the death of certain cancer cells, including prostate cancer celllines (Batra S, Popper L D, Hartley-Asp B. Prostate. 1991, 19: 299).Similar studies are conducted using sodium, potassium, pH, etcindicators.

Due to its homology to an oxidoreductase, 98P4B6 can participate inimparting drug resistance by mobilizing and transporting smallmolecules. The effect of 98P4B6 on small molecule transport isinvestigated using a modified MDR assay. Control and 98P4B6 expressingcells are loaded with a fluorescent small molecule such as calcein AM.Extrusion of calcein from the cell is measured by examining thesupernatants for fluorescent compound. MDR-like activity is confirmedusing MDR inhibitors.

When 98P4B6 functions as a transporter, it is used as target fordiagnostic, prognostic, preventative and/or therapeutic purposes.

Example 48 Involvement in Tumor Progression

The 98P4B6 gene can contribute to the growth of cancer cells. The roleof 98P4B6 in tumor growth is confirmed in a variety of primary andtransfected cell lines including prostate as well as NIH 3T3 cellsengineered to stably express 98P4B6. Parental cells lacking 98P4B6 andcells expressing 98P4B6 are evaluated for cell growth using awell-documented proliferation assay (Fraser S P, Grimes J A, Djamgoz MB. Prostate. 2000;44:61, Johnson D E, Ochieng J, Evans S L. AnticancerDrugs. 1996, 7:288).

To confirm the role of 98P4B6 in the transformation process, its effectin colony forming assays is investigated. Parental NIH-3T3 cells lacking98P4B6 are compared to NIH-3T3 cells expressing 98P4B6, using a softagar assay under stringent and more permissive conditions (Song Z. etal. Cancer Res. 2000;60:6730).

To confirm the role of 98P4B6 in invasion and metastasis of cancercells, a well-established assay is used, e.g., a Transwell Insert Systemassay (Becton Dickinson) (Cancer Res. 1999; 59:6010). Control cells,including prostate and fibroblast cell lines lacking 98P4B6 are comparedto cells expressing 98P4B6. Cells are loaded with the fluorescent dye,calcein, and plated in the top well of the Transwell insert coated witha basement membrane analog. Invasion is determined by fluorescence ofcells in the lower chamber relative to the fluorescence of the entirecell population.

98P4B6 can also play a role in cell cycle and apoptosis. Parental cellsand cells expressing 98P4B6 are compared for differences in cell cycleregulation using a well-established BrdU assay (Abdel-Malek Z A. J CellPhysiol. 1988, 136:247). In short, cells are grown under both optimal(full serum) and limiting (low serum) conditions are labeled with BrdUand stained with anti-BrdU Ab and propidium iodide. Cells are analyzedfor entry into the G1, S, and G2M phases of the cell cycle.Alternatively, the effect of stress on apoptosis is evaluated in controlparental cells and cells expressing 98P4B6, including normal and tumorprostate cells. Engineered and parental cells are treated with variouschemotherapeutic agents, such as etoposide, flutamide, etc, and proteinsynthesis inhibitors, such as cycloheximide. Cells are stained withannexin V-FITC and cell death is measured by FACS analysis. Themodulation of cell death by 98P4B6 can play a critical role inregulating tumor progression and tumor load.

When 98P4B6 plays a role in cell growth, transformation, invasion orapoptosis, it is used as a target for diagnostic, prognostic,preventative and/or therapeutic purposes.

Example 49 Involvement in Angiogenesis

Angiogenesis or new capillary blood vessel formation is necessary fortumor growth (Hanahan D, Folkman J. Cell. 1996, 86:353; Folkman J.Endocrinology. 1998 139:441). Based on the effect of phsophodieseteraseinhibitors on endothelial cells, 98P4B6 plays a role in angiogenesis(DeFouw L et al, Microvasc Res 2001, 62:263). Several assays have beendeveloped to measure angiogenesis in vitro and in vivo, such as thetissue culture assays endothelial cell tube formation and endothelialcell proliferation. Using these assays as well as in vitroneo-vascularization, the role of 98P4B6 in angiogenesis, enhancement orinhibition, is confirmed.

For example, endothelial cells engineered to express 98P4B6 areevaluated using tube formation and proliferation assays. The effect of98P4B6 is also confirmed in animal models in vivo. For example, cellseither expressing or lacking 98P4B6 are implanted subcutaneously inimmunocompromised mice. Endothelial cell migration and angiogenesis areevaluated 5-15 days later using immunohistochemistry techniques. 98P4B6affects angiogenesis, and it is used as a target for diagnostic,prognostic, preventative and/or therapeutic purposes.

Example 50 Regulation of Transcription

The localization of 98P4B6 and its similarity to hydrolases as well asits Ets motif (v.7) indicate that 98P4B6 is effectively used as amodulator of the transcriptional regulation of eukaryotic genes.Regulation of gene expression is confirmed, e.g., by studying geneexpression in cells expressing or lacking 98P4B6. For this purpose, twotypes of experiments are performed.

In the first set of experiments, RNA from parental and 98P4B6-expressingcells are extracted and hybridized to commercially available gene arrays(Clontech) (Smid-Koopman E et al. Br J Cancer. 2000. 83:246). Restingcells as well as cells treated with FBS or androgen are compared.Differentially expressed genes are identified in accordance withprocedures known in the art. The differentially expressed genes are thenmapped to biological pathways (Chen K et al. Thyroid. 2001. 11:41.).

In the second set of experiments, specific transcriptional pathwayactivation is evaluated using commercially available (Stratagene)luciferase reporter constructs including: NFkB-luc, SRE-luc, ELK1-luc,ARE-luc, p53-luc, and CRE-luc. These transcriptional reporters containconsensus binding sites for known transcription factors that liedownstream of well-characterized signal transduction pathways, andrepresent a good tool to ascertain pathway activation and screen forpositive and negative modulators of pathway activation.

Thus, 98P4B6 plays a role in gene regulation. When 98P4B6 is involved ingene regulation it is used as a target for diagnostic, prognostic,preventative and/or therapeutic purposes.

Example 51 Protein—Protein Association

Several 6TM proteins have been shown to interact with other proteins,thereby regulating signal transduction, gene transcription,transformation, and cell adhesion. Using immunoprecipitation techniquesas well as two yeast hybrid systems, proteins are identified thatassociate with 98P4B6. Immunoprecipitates from cells expressing 98P4B6and cells lacking 98P4B6 are compared for specific protein-proteinassociations.

Studies are performed to confirm the extent of association of 98P4B6with effector molecules, such as nuclear proteins, transcriptionfactors, kinases, phsophates etc. Studies comparing 98P4B6 positive and98P4B6 negative cells as well as studies comparing unstimulated/restingcells and cells treated with epithelial cell activators, such ascytokines, growth factors, androgen and anti-integrin Ab reveal uniqueinteractions.

In addition, protein-protein interactions are confirmed using two yeasthybrid methodology (Curr Opin Chem Biol. 1999, 3:64). A vector carryinga library of proteins fused to the activation domain of a transcriptionfactor is introduced into yeast expressing a 98P4B6-DNA-binding domainfusion protein and a reporter construct. Protein-protein interaction isdetected by calorimetric reporter activity. Specific association witheffector molecules and transcription factors directs one of skill to themode of action of 98P4B6, and thus identifies therapeutic, prognostic,preventative and/or diagnostic targets for cancer. This and similarassays are also used to identify and screen for small molecules thatinteract with 98P4B6.

Thus it is found that 98P4B6 associates with proteins and smallmolecules. Accordingly, 98P4B6and these proteins and small molecules areused for diagnostic, prognostic, preventative and/or therapeuticpurposes.

Throughout this application, various website data content, publications,patent applications and patents are referenced. (Websites are referencedby their Uniform Resource Locator, or URL, addresses on the World WideWeb.) The disclosures of each of these references are herebyincorporated by reference herein in their entireties.

The present invention is not to be limited in scope by the embodimentsdisclosed herein, which are intended as single illustrations ofindividual aspects of the invention, and any that are functionallyequivalent are within the scope of the invention. Various modificationsto the models and methods of the invention, in addition to thosedescribed herein, will become apparent to those skilled in the art fromthe foregoing description and teachings, and are similarly intended tofall within the scope of the invention. Such modifications or otherembodiments can be practiced without departing from the true scope andspirit of the invention.

TABLE I Tissues that Express 98P4B6: a. Malignant Tissues a Bladder b.Breast c. Cervix d. Colon e. Kidney f. Lung g. Ovary h. Pancreas i.Prostate j. Stomach k. Uterus

TABLE II Amino Acid Abbreviations SINGLE LETTER THREE LETTER FULL NAME FPhe phenylalanine L Leu leucine S Ser serine Y Tyr tyrosine C Cyscysteine W Trp tryptophan P Pro proline H His histidine Q Gln glutamineR Arg arginine I Ile isoleucine M Met methionine T Thr threonine N Asnasparagine K Lys lysine V Val valine A Ala alanine D Asp aspartic acid EGlu glutamic acid G Gly glycine

TABLE III Amino Acid Substitution Matrix Adapted from the GCG Software9.0 BLOSUM62 amino acid substitution matrix (block substitution matrix).The higher the value, the more likely a substitution is found inrelated, natural proteins. A C D E F G H I K L M N P Q R S T V W Y . 4 0−2 −1 −2 0 −2 −1 −1 −1 −1 −2 −1 −1 −1 1 0 0 −3 −2 A 9 −3 −4 −2 −3 −3 −1−3 −1 −1 −3 −3 −3 −3 −1 −1 −1 −2 −2 C 6 2 −3 −1 −1 −3 −1 −4 −3 1 −1 0 −20 −1 −3 −4 −3 D 5 −3 −2 0 −3 1 −3 −2 0 −1 2 0 0 −1 −2 −3 −2 E 6 −3 −1 0−3 0 0 −3 −4 −3 −3 −2 −2 −1 1 3 F 6 −2 −4 −2 −4 −3 0 −2 −2 −2 0 −2 −3 −2−3 G 8 −3 −1 −3 −2 1 −2 0 0 −1 −2 −3 −2 2 H 4 −3 2 1 −3 −3 −3 −3 −2 −1 3−3 −1 I 5 −2 −1 0 −1 1 2 0 −1 −2 −3 −2 K 4 2 −3 −3 −2 −2 −2 −1 1 −2 −1 L5 −2 −2 0 −1 −1 −1 1 −1 −1 M 6 −2 0 0 1 0 −3 −4 −2 N 7 −1 −2 −1 −1 −2 −4−3 P 5 1 0 −1 −2 −2 −1 Q 5 −1 −1 −3 −3 −2 R 4 1 −2 −3 −2 S 5 0 −2 −2 T 4−3 −1 V 11 2 W 7 Y

TABLE IV HLA Class I/II Motifs/Supermotifs TABLE IV (A): HLA Class ISupermotifs/Motifs POSITION POSITION POSITION C Terminus (PrimarySUPERMOTIF 2 (Primary Anchor) 3 (Primary Anchor) Anchor A1 T ILVMS FWYA2 LIVM ATQ IV MATL A3 VSMA TLI RK A24 YF WIVLMT FI YWLM B7 P VILF MWYAB27 RHK FYL WMIVA 644 E D FWYLIMVA B58 ATS FWY LIVMA B62 QL IVMP FWYMIVLA MOTIFS A1 TSM Y A1 DE AS Y A2.1 LM VQIAT V LIMAT A3 LMVISATF CGDKYR HFA A11 VTMLISAGN CDF K RYH A24 YFWM FLIW A*3101 MVT ALIS R K A*3301MVALF IST RK A*6801 AVT MSLI RK B*0702 P LMF WYAIV B*3501 P LMFWY IVAB51 P LIVF WYAM B*5301 P IMFWY ALV B*5401 P ATIV LMFWY Bolded residuesare preferred, italicized residues are less preferred: A peptide isconsidered motif-bearing if it has primary anchors at each primaryanchor position for a motif or supermotif as specified in the abovetable. TABLE IV (B): HLA Class II Supermotif 1 6 9 W, F, Y, V, .I, L A,V, I, L, P, C, S, T A, V, I, L, C, S, T, M, Y TABLE IV (C): HLA Class IIMotifs MOTIFS 1° anchor 1 2 3 4 5 1° anchor 6 7 8 9 DR4 preferredFMYLIVW M T W I VSTCPALIM MH MH deleterious R WDE DR1 preferred MFLIVWYC CH PAMQ CWD VMATSPLIC M AVM deleterious FD GDE D DR7 preferred MFLIVWYM W A IVMSACTPL M IV deleterious C G GRD N G DR3 MOTIFS 1° anchor 1 2 31° anchor 4 5 1° anchor 6 Motif a preferred LIVMFY D Motif b preferredLIVMFAY DNQEST KRH DR Supermotif MFLIVWY VMSTACPLI Italicized residuesindicate less preferred or “tolerated” residues TABLE IV (D): HLA ClassI Supermotifs SUPER- MOTIFS POSITION: 1 2 3 4 5 6 7 8 C-terminus A11° Anchor 1° Anchor TILVMS FWY A2 1° Anchor 1° Anchor LIVMATQ LIVMAT A3Preferred DE (3/5); 1° Anchor YFW YFW YFW P 1° Anchor deleterious P(5/5) VSMATLI (4/5) (3/5) (4/5) (4/5) RK DE (4/5) A24 1° Anchor1° Anchor YFWIVLMT FIYWLM B7 Preferred FWY (5/5) 1° Anchor FWY FWY1° Anchor deleterious LIVM (3/5) P (4/5) (3/5) VILFMWYA DE (3/5); DE GQN DE P (5/5); (3/5) (4/5) (4/5) (4/5) G (4/5); A (3/5); QN (3/5) B271° Anchor 1° Anchor RHK FYLWMIVA B44 1° Anchor 1° Anchor ED FWYLIMVA B581° Anchor 1° Anchor ATS FWYLIVMA B62 1° Anchor 1° Anchor QLIVMP FWYMIVLAItalicized residues indicate less preferred or “tolerated” residuesTABLE IV (E): HLA Class I Motifs 9 or C- POSITION 1 2 3 4 5 6 7 8C-terminus terminus A1 preferred GFYW 1° Anchor DEA YFW P DEQN YFW1° Anchor 9-mer STM Y deleterious DE RHKLIVMP A G A A1 preferred GRHKASTCLIVM 1° Anchor GSTC ASTC LIVM DE 1° Anchor 9-mer DEAS Y deleteriousA RHKDEPYFW DE PQN RHK PG GP A1 preferred YFW 1° Anchor DEAQN A YFWQNQNA PASTC GDE P 1° Anchor 10- STM Y mer deleterious GP RHKGLIVM DE RHKRHKYFW RHK A A1 preferred YFW STCLIVM 1° Anchor A YFW G PG G YFW1° Anchor 10- DEAS Y mer deleterious RHK RHKDEPYEW P PRHK QN A2.1preferred YFW 1° Anchor YFW STC YFW RKH A P 1° Anchor 9-mer LMIVQATVLIMAT deleterious DEP DERKH DERKH POSI- C-Ter- TION: 1 2 3 4 5 6 7 8 9minus A2.1 preferred AYFW 1° Anchor LVIM G P G RHK FYWL 1° 10- LMIVQATVIM Anchor mer VLIMA T deleterious DEP DE RKHA DERKHRKH A3 preferred RHK1° Anchor YFW PRHKYF A YFW P 1° Anchor LMVISATFCGD W KYRHFA deleteriousDEP DE A11 preferred A 1° Anchor YFW YFW A YFW YFW P 1° AnchorVTLMISAGNCD KRYH F deleterious DEP A G A24 preferred YFWRHK 1° Anchor DESTC QNP DERHKG YFW YFW 1° Anchor 9-mer YFWM FLIW deleterious DEG G AQNA24 Preferred 1° Anchor GDE P YFWP DE P QN DEA 1° 10- YFWIM Anchor merFLIW Delete- QN RHK A rious A3101 Preferred RHK 1° Anchor YFW P ADE YFWYFW AP 1° Anchor MVTALIS RK Delete- DEP DE DE DE DE rious A3301Preferred GP 1° Anchor YFW AYEW 1° Anchor MVALFIST RK Delete- DE riousA6801 Preferred YFWSTC 1° Anchor DEG YFWLIV YFW P 1° Anchor AVTMSLI M RKdeleterious GP RHK A B0702 Preferred RHKFWY 1° Anchor RHK DE RHK RHK RHKPA 1° Anchor P LMFWYAI V deleterious DEQNP DEP DE GDE QN DE B3501Preferred FWYLIVM 1° Anchor FWY FWY 1° P Anchor LMFWYIV A 9 POSI- or C-TION 1 2 3 4 5 6 7 8 terminus A1 preferred GFYW 1° Anchor DEA YFW G PDEQN YFW 1° Anchor 9-mer STM Y deleterious DE RHKLIVMP A A A1 preferredGRHK ASTCLIVM 1° Anchor GSTC PQN ASTC LIVM DE 1° Anchor 9-mer DEAS Ydeleterious A RHKDEPYFW DE G RHK PG GP deleterious AGP G B51 PreferredLIVMFWY 1° Anchor FWY STC FWY G G FWY 1° Anchor P LIVFWYA M deleteriousAGPDER DE DEQN GDE HKSTC B5301 preferred LIVMFWY 1° Anchor FWY STC FWY GLIVMFWYFWY DE 1° Anchor P IMFWYA LV deleterious AGPQN P RHKQN DE B5401preferred FWY 1° Anchor FWYLIVM LIVM DE ALIVM FWYA 1° Anchor P P ATIVLMFWY deleterious GPQNDE GDESTC RHKDE QNDGE DE TABLE IV (F): Summary ofHLA-supertypes Overall phenotypic frequencies of HLA-supertypes indifferent ethnic populations Specificity Phenotypic frequency SupertypePosition 2 C-Terminus Caucasian N.A. Black Japanese Chinese HispanicAverage B7 P AILMVFWY 43.2 55.1 57.1 43.0 49.3 49.5 A3 AILMVST RK 37.542.1 45.8 52.7 43.1 44.2 A2 AILMVT AILMVT 45.8 39.0 42.4 45.9 43.0 42.2A24 YF (WIVLMT) FI (YWLM) 23.9 38.9 58.6 40.1 38.3 40.0 B44 E (D)FWYLIMVA 43.0 21.2 42.9 39.1 39.0 37.0 A1 TI (LVMS) FWY 47.1 16.1 21.814.7 26.3 25.2 B27 RHK FYL (WMI) 28.4 26.1 13.3 13.9 35.3 23.4 B62 QL(IVMP) FWY (MIV) 12.6 4.8 36.5 25.4 11.1 18.1 B58 ATS FWY (LIV) 10.025.1 1.6 9.0 5.9 10.3 TABLE IV (G): Calculated population coverageafforded by different HLA-supertype combinations HLA-supertypesPhenotypic frequency Caucasian N.A Blacks Japanese Chinese HispanicAverage A2, A3 and B7 83.0 86.1 87.5 88.4 86.3 86.2 A2, A3, B7, A24, B4499.5 98.1 100.0 99.5 99.4 99.3 and A1 99.9 99.6 100.0 99.8 99.9 99.8 A2,A3, B7, A24, B44, A1, B27, B62, and B 58 Motifs indicate the residuesdefining supertype specificites. The motifs incorporate residuesdetermined on the basis of published data to be recognized by multiplealleles within the supertype. Residues within brackets are additionalresidues also predicted to be tolerated by multiple alleles within thesupertype.

TABLE V Frequently Occurring Motifs avrg. % Name identity DescriptionPotential Function zf-C2H2 34% Zinc finger, C2H2 type Nucleicacid-binding protein functions as transcription factor, nuclear locationprobable cytochrome_b_N 68% Cytochrome b(N- membrane bound oxidase,generate terminal)/b6/petB superoxide Ig 19% Immunoglobulin domaindomains are one hundred amino acids long and include a conservedintradomain disulfide bond. WD40 18% WD domain, G-beta repeat tandemrepeats of about 40 residues, each containing a Trp-Asp motif. Functionin signal transduction and protein interaction PDZ 23% PDZ domain mayfunction in targeting signaling molecules to sub-membranous sites LRR28% Leucine Rich Repeat short sequence motifs involved inprotein-protein interactions Pkinase 23% Protein kinase domain conservedcatalytic core common to both serine/threonine and tyrosine proteinkinases containing an ATP binding site and a catalytic site PH 16% PHdomain pleckstrin homology involved in intracellular signaling or asconstituents of the cytoskeleton EGF 34% EGF-like domain 30-40amino-acid long found in the extracellular domain of membrane- boundproteins or in secreted proteins Rvt 49% Reverse transcriptase(RNA-dependent DNA polymerase) Ank 25% Ank repeat Cytoplasmic protein,associates integral membrane proteins to the cytoskeleton Oxidored_q132% NADH- membrane associated. Involved in Ubiquinone/plastoquinoneproton translocation across the (complex I), various chains membraneEfhand 24% EF hand calcium-binding domain, consists of a 12 residue loopflanked on both sides by a 12 residue alpha-helical domain Rvp 79%Retroviral aspartyl Aspartyl or acid proteases, centered on protease acatalytic aspartyl residue Collagen 42% Collagen triple helix repeatextracellular structural proteins involved (20 copies) in formation ofconnective tissue. The sequence consists of the G-X-Y and thepolypeptide chains forms a triple helix. Fn3 20% Fibronectin type IIIdomain Located in the extracellular ligand- binding region of receptorsand is about 200 amino acid residues long with two pairs of cysteinesinvolved in disulfide bonds 7tm_1 19% 7 transmembrane receptor sevenhydrophobic transmembrane (rhodopsin family) regions, with theN-terminus located extracellularly while the C-terminus is cytoplasmic.Signal through G proteins

TABLE VI Motifs and Post-translational Modifications of 98P4B6 cAMP- andcGMP-dependent protein kinase phosphorylation site. 176-179 RKET (SEQ IDNO: 114) Protein kinase C phosphorylation site. 235-237 SVK Caseinkinase II phosphorylation site. 9-12 SATD (SEQ ID NO: 115) 50-53 TVME(SEQ ID NO: 116) 130-133 SCTD (SEQ ID NO: 117) 172-175 SPEE (SEQ ID NO:118) N-myristoylation site. 14-19 GLSIST (SEQ ID NO: 119) G-proteincoupled receptors family 1 signature. 52-68 MESSVLLAMAFDRFVAV (SEQ IDNO: 120)

TABLE VII Search Peptides v.1 aa1-454 (SEQ ID NO: 121) 9-mers, 10-mersand 15-mers MESISMMGSP KSLSETCLPN GINGIKDARK VTVGVIGSGD FAKSLTIRLIRCGYHVVIGS RNPKFASEFF PHVVDVTHHE DALTKTNIIF VAIHREHYTS LWDLRHLLVGKILIDVSNNM RINQYPESNA EYLASLFPDS LTVKGFNVVS AWALQLGPKD ASRQVYICSNNIQARQQVIE LARQLNFIPI DLGSLSSARE IENLPLRLFT LWRGPVVVAI SLATFFFLYSFVRDVIHPYA RNQQSDFYKI PIEIVNKTLP IVAITLLSLV YLAGLLAAAY QLYYGTKYRRFPPWLETWLQ CRKQLGLLSF FFANVHVAYS LCLPMRRSER YLFLNMAYQQ VHANIENSWNEEEVWRIEMY TSFGIMSLGL LSLLAVTSIP SVSNALHWRE FSFIQSTLGY VALLISTFHVLIYGWKRAFE EEYYRFYTPP NFVLALVLPS IVILDLLQLC RYPD v.2 aa1-45 (SEQ ID NO:122) 9-mers, 10-mers, 15-mers SGSPGLQALSL SLSSGFTPFS CLSLPSSWDYRCPPPCPADF FLYF v.5, (one aa diff at 211 and different c-terminal) PartA 9-mers: aa203-219 NLPLRLFTFWRGPVVVA (SEQ ID NO: 123) 10-mers:aa202-220 ENLPLRLFTFWRGPVVVAI (SEQ ID NO: 124) 15-mers: aa197-225SAREIENLPLRLFTFWRGPVVVAISLATF (SEQ ID NO: 125) Part B 9-mers: aa388-419WREFSFIQIFCSFADTQTELELEFVFLLTLLL (SEQ ID NO: 126) 10-mers: aa387-419NWREFSFIQIFCSFADTQTELELEFVFLLTLLL (SEQ ID NO: 127) 15-mers: aa382-419VSNALNWREFSFIQIFCSFADTQTELELEFVFLLTLLL (SEQ ID NO: 128) v.6, (differentfrom our original in 445-490) 9-mers; aa447-490 (SEQ ID NO: 129)VLPSIVILGKIILFLPCISRKLKRIKKGWEKSQFLEEGIGGTIPHVSPERVTVM 10-mers:aa446-490 (SEQ ID NO: 130)LVLPSIVILGKIILFLPCISRKLKRIKKGWEKSQFLEEGIGGTIPHVSPERVTVM 15-mers:aa441-490 (SEQ ID NO: 131)NFVLALVLPSIVILGKIILFLPCISRKLKRIKKGWEKSQFLEEGIGGTTPHVSPERVTVM v.7,(deleting our original 340-394, 392-576 is different) Part A 9-mers:aa334-350 FLNMAYQQSTLGYVALL (SEQ ID NO: 132) 10-mers: aa333-351LFLNMAYQQSTLGYVALLI (SEQ ID NO: 133) 15-mers: aa328-355RSERYLFLNMAYQQSTLGYVALLISTFHV (SEQ ID NO: 134) Part B 9-mers: aa384576(SEQ ID NO: 135)PSIVILDLSVEVLASPAAAWKCLGANILRGGLSETVLPIEWQQDRKIPPLSTPPPPAMWTEEAGATAEAQESGIRNKSSSSSQIPVVGVVTEDDEAQDSIDPPESPDRALKAANSWRNPVLPHThGVGPLWEFLLRLLKSQAASGTLSLAFTSWSLGEFLGSGTWMKLETIILSKLTQEQKSKHCMFSLISGS 10-mers: aa383-576 (SEQ ID NO: 136)LPSIVILDLSVEVLASPAAAWKCLGANILRGGLSEIVLPIEWQQDRKIPPLSTPPPPAMWTEEAGATAEAQESGIRNKSSSSSQIPVVGVVTEDDEAQDSIDPPESPDRALKAANSWRNPVLPHTNGVGPLWEFLLRLLKSQAASGTLSLAFTSWSLG EFLGSGTWMK LETIILSKLT QEQKSKHCMFSLISGS 15-mers: aa378-576 (SEQ ID NO: 137)VLALVLPSIVILDLSVEVLASPAAAWKCLGANILRGGLSEIVLPIEWQQDRKIPPLSTPPPPAMWTEEAGATAEAQESGIRNKSSSSSQIPVVGVVTEDDEAQDSIDPPESPDRALKAANSWRNPVLPHTNGVGPLWEFLLRLLKSQAASGTLSLAFTSWSLG EFLGSGTWMK LETIILSKLT QEQKSKHCMFSLISGS v.8, SNP variant of v.6, one aa different at 475 9-mers:aa466-482 KSQFLEEGMGGTIPHVS (SEQ ID NO: 138) 10-mers: aa465-483EKSQFLEEGMGGTIPHVSP (SEQ ID NO: 139) 15-mers: aa460-489IKKGWEKSQFLEEGMGGTIPHVSPERVTV (SEQ ID NO: 140) V13 9-mers: aa9-25SPKSLSETFLPNGINGI (SEQ ID NO: 141) 10-mers: aa8-26 GSPKSLSETFLPNGINGIK(SEQ ID NO: 142) 15-mers: aa3-31 SISMMGSPKSLSETFLPNGINGIKDARKV (SEQ IDNO: 143) v.14 9-mers: aa203-219 NLPLRLFTFWRGPVVVA (SEQ ID NO: 144)10-mers: aa202-220 ENLPLRLFTFWRGPVVVAI (SEQ ID NO: 145) 15-mers:aa197-225 SAREIENLPLRLFTFWRGPVVVAISLATF (SEQ ID NO: 146) V.21 9-mers557-572 SKLTQEQKTKHCMFSLI (SEQ ID NO: 147) 10-mers 556-573LSKLTQEQKTKHCMFSLIS (SEQ ID NO: 148) 15-mers 551-576LETIILSKLTQEQKTKHCMFSLISGS (SEQ ID NO: 149) V.25 9-mers aa 447-463ILFLPCISQKLKRIKKG (SEQ ID NO: 150) 10-mers aa 446-464IILFLPCISQKLKRIKKGW (SEQ ID NO: 151) 15-mers aa440-468VILGKIILFLPCISQKLKRIKKGWEKSQF (SEQ ID NO: 152)

TABLE VIII V1-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 443 ILDLLQLCR 25.000 129 NAEYLASLF9.000 294 WLETWLQCR 9.000 113 LIDVSNNMR 5.000 200 EIENLPLRL 4.500 244QSDFYKIPI 3.750 405 ISTFHVLIY 3.750 13 LSETCLPNG 2.700 221 SLATFFFLY2.500 263 AITLLSLVY 2.500 276 LAAAYQLYY 2.500 419 FEEEYYRFY 2.250 155QLGPKDASR 2.000 66 ASEFFPHVV 1.35 272 LAGLLAAAY 1.000 35 VIGSGDFAK 1.000178 VIELARQLN 0.900 356 RIEMYISFG 0.900 418 AFEEEYYRF 0.900 319YSLCLPMRR 0.750 43 KSLTIRLIR 0.750 327 RSERYLFLN 0.675 427 YTPPNFVLA0.500 304 QLGLLSFFF 0.500 257 KTLPIVAIT 0.500 135 SLFPDSLIV 0.500 223ATFFFLYSF 0.500 275 LLAAAYQLY 0.500 385 ALNWREFSF 0.500 219 AISLATFFF0.500 16 TCLPNGING 0.500 90 FVAIHREHY 0.500 87 NIIFVAIHR 0.500 249KIPIEIVNK 0.400 137 FPDSLIVKG 0.250 189 PIDLGSLSS 0.250 241 RNQQSDFYK0.250 351 EEEVWRIEM 0.225 349 WNEEEVWRI 0.225 125 YPESNAEYL 0.225 420EEEYYRFYT 0.225 388 WREFSFIQS 0.225 198 AREIENLPL 0.225 57 VIGSRNPKF0.200 56 VVIGSRNPK 0.200 217 VVAISLATF 0.200 3 SISMMGSPK 0.200 417RAFEEEYYR 0.200 436 LVLPSIVIL 0.200 377 TSIPSVSNA 0.150 158 PKDASRQVY0.125 101 LWDLRHLLV 0.125 117 SNNMRINQY 0.125 392 SFIQSTLGY 0.125 202ENLPLRLFT 0.125 330 RYLFLNMAY 0.125 38 SGDFAKSLT 0.125 98 YTSLWDLRH0.125 406 STFHVLIYG 0.125 218 VAISLATFF 0.100 167 ACSNNIQAR 0.100 400YVALLISTF 0.100 235 VIHPYARNQ 0.100 381 SVSNALNWR 0.100 22 INGIKDARK0.100 21 GINGIKDAR 0.100 281 QLYYGTKYR 0.100 322 CLPMRRSER 0.100 411LIYGWKRAF 0.100 191 DLGSLSSAR 0.100 409 HVLIYGWKR 0.100 344 NIENSWNEE0.090 251 PIEIVNKTL 0.090 308 LSFFFAMVH 0.075 195 LSSAREIEN 0.075 116VSNNMRINQ 0.075 280 YQLYYGTKY 0.075 220 ISLATFFFL 0.075 175 RQQVIELAR0.075 127 ESNAEYLAS 0.075 432 FVLALVLPS 0.050 12 SLSETCLPN 0.050 106HLLVGKILI 0.050 311 FFAMVHVAY 0.050 269 LVYLAGLLA 0.050 216 VVVAISLAT0.050 124 QYPESNAEY 0.050 166 YICSNNIQA 0.050 258 TLPIVAITL 0.050 18LPNGINGIK 0.050 435 ALVLPSIVI 0.050 25 IKDARKVTV 0.050 73 VVDVTHHED0.050 222 LATFFFLYS 0.050 184 QLNFIPIDL 0.050 367 SLGLLSLLA 0.050 46TIRLIRCGY 0.050 306 GLLSFFFAM 0.050 261 IVAITLLSL 0.050 203 NLPLRLFTL0.050

TABLE VIII V2-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 23 LSLPSSWDY 7.500 33 CPPPCPADF0.500 36 PCPADFFLY 0.250 9 LSLSLSSGF 0.150 37 CPADFFLYF 0.125 17FTPFSCLSL 0.125 24 SLPSSWDYR 0.100 12 SLSSGFTPF 0.100 14 SSGFTPFSC 0.0755 GLQALSLSL 0.050 7 QALSLSLSS 0.050 13 LSSGFTPFS 0.030 2 GSPGLQALS 0.03020 FSCLSLPSS 0.030 1 SGSPGLQAL 0.025 32 RCPPPCPAD 0.020 35 PPCPADFFL0.013 3 SPGLQALSL 0.013 21 SCLSLPSSW 0.010 8 ALSLSLSSG 0.010 10SLSLSSGFT 0.010 11 LSLSSGFTP 0.007 25 LPSSWDYRC 0.005 16 GFTPFSCLS 0.00528 SWDYRCPPP 0.005 31 YRCPPPCPA 0.005 15 SGFTPFSCL 0.003 34 PPPCPADFF0.003 6 LQALSLSLS 0.002 22 CLSLPSSWD 0.001 19 PFSCLSLPS 0.000 18TPFSCLSLP 0.000 4 PGLQALSLS 0.000 27 SSWDYRCPP 0.000 26 PSSWDYRCP 0.00029 WDYRCPPPC 0.000 30 DYRCPPPCP 0.000

TABLE VIII V5A-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight Start Subsequence Score 1 NLPLRLFTF 0.500 7 FTFWRGPVV 0.050 3PLRLFTFWR 0.005 5 RLFTFWRGP 0.001 6 LFTFWRGPV 0.001 4 LRLFTFWRG 0.001 2LPLRLFTFW 0.000 9 FWRGPVVVA 0.000 8 TFWRGPVVV 0.000

TABLE VIII V5B-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 21 ELEFVFLLT 4.500 17 QTELELEFT2.250 19 ELELEFVFL 1.800 1 WREFSFIQI 0.225 16 TQTELELEF 0.075 4FSFIQIFCS 0.075 24 FVFLLTLLL 0.050 13 FADTQTELE 0.050 18 TELELEFVF 0.0258 QIFCSFADT 0.020 10 FCSFADTQT 0.010 6 FIQIFCSFA 0.010 2 TEFSFIQIF 0.0055 SFIQIFCSF 0.005 15 DTQTELELE 0.003 20 LELEFVFLL 0.003 22 LEFVFLLTL0.003 14 ADTQTELEL 0.003 3 EFSFIQIFC 0.003 11 CSFADTQTE 0.002 7IQIFCSFAD 0.001 23 EFVFLLTLL 0.001 12 SFADTQTEL 0.001 9 IFCSFADTQ 0.001

TABLE VIII V6-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight Start Subsequence Score 34 FLEEGIGGT 0.900 12 ILFLPCISR 0.5006 VILGKIILF 0.500 2 LPSIVILGK 0.250 42 TIPHVSPER 0.200 45 HVSPERVTV0.200 13 LFLPCISRK 0.100 16 PCISRKLKR 0.050 1 VLPSIVILG 0.050 15LPCISRKLK 0.050 5 IVILGKIIL 0.050 35 LEEGIGGTI 0.045 41 GTIPHVSPE 0.02538 GIGGTIPHV 0.020 10 KIILFLPCI 0.020 31 KSQFLEEGI 0.015 46 VSPERVTVM0.015 37 EGIGGTIPH 0.013 4 SIVILGKII 0.010 14 FLPCISRKL 0.010 11IILFLPCIS 0.010 19 SRKLKRIKK 0.005 7 ILGKIILFL 0.005 26 KKGWEKSQF 0.00518 ISRKLKRIK 0.003 33 QFLEEGIGG 0.003 43 IPHVSPERV 0.003 9 GKIILFLPC0.003 39 IGGTIPHVS 0.003 28 GWEKSQFLE 0.002 3 PSIVILGKI 0.002 32SQFLEEGIG 0.002 23 KRIKKGWEK 0.001 17 CISRKLKRI 0.001 40 GGTIPHVSP 0.00130 EKSQFLEEG 0.001 27 KGWEKSQFL 0.000 8 LGKIILFLP 0.000 24 RIKKGWEKS0.000 21 KLKRIKKGW 0.000 36 EEGIGGTIP 0.000 44 PHVSPERVT 0.000 20RKLKRIKKG 0.000 25 IKKGWEKSQ 0.000 29 WEKSQFLEE 0.000 22 LKRIKKGWE 0.000

TABLE VIII V7A-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 5 LSETFLPNG 2.700 4 SLSETFLPN 0.0507 ETFLPNGIN 0.025 8 TFLPNGING 0.025 9 FLPNGINGI 0.010 3 KSLSETFLP 0.0071 SPKSLSETF 0.003 6 SETFLPNGI 0.001 2 PKSLSETFL 0.000

TABLE VIII V7B-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight Start Subsequence Score 5 AYQQSTLGY 0.125 9 STLGYVALL 0.050 8QSTLGYVAL 0.030 1 FLNMAYQQS 0.010 4 MAYQQSTLG 0.010 3 NMAYQQSTL 0.005 7QQSTLGYVA 0.003 2 LNMAYQQST 0.003 6 YQQSTLGYV 0.002

TABLE VIII V7C-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 167 KLETIILSK 90.000 59 WTEEAGATA4.500 13 LASPAAAWK 4.000 69 AQESGIRNK 2.700 38 PIEWQQDRK 1.800 66TAEAQESGI 0.900 9 SVEVLASPA 0.900 143 ASGTLSLAF 0.750 99 SIDPPESPD 0.50051 STPPPPAMW 0.500 5 ILDLSVEVL 0.500 21 KCLGANILR 0.500 90 VTEDDEAQD0.450 50 LSTPPPPAM 0.300 32 LSEIVLPIE 0.270 151 FTSWSLGEF 0.250 156LGEFLGSGT 0.225 175 KLTQEQKSK 0.200 159 FLGSGTWMK 0.200 177 TQEQKSKHC0.135 128 GPLWEFLLR 0.125 145 GTLSLAFTS 0.125 52 TPPPPAMWT 0.125 126GVGPLWEFL 0.100 35 IVLPIEWQQ 0.100 100 IDPPESPDR 0.100 104 ESPDRALKA0.075 78 SSSSSQIPV 0.075 154 WSLGEFLGS 0.075 131 WEFLLRLLK 0.050 22CLGANILRG 0.050 68 EAQESGIRN 0.050 184 HCMFSLISG 0.050 7 DLSVEVLAS 0.050170 TIILSKLTQ 0.050 2 SIVILDLSV 0.050 17 AAAWKCLGA 0.050 141 QAASGTLSL0.050 123 HTNGVGPLW 0.050 31 GLSEIVLPI 0.050 130 LWEFLLRLL 0.045 173LSKLTQEQK 0.030 80 SSSQIPVVG 0.030 81 SSQIPVVGV 0.030 79 SSSSQIPVV 0.030125 NGVGPLWEF 0.025 65 ATAEAQESG 0.025 37 LPIEWQQDR 0.025 92 EDDEAQDSI0.025 169 ETIILSKLT 0.025 176 LTQEQKSKH 0.025 91 TEDDEAQDS 0.025 102PPESPDRAL 0.022 103 PESPDRALK 0.020 11 EVLASPAAA 0.020 83 QIPVVGVVT0.020 4 VILDLSVEV 0.200 12 VLASPAAAW 0.020 42 QQDRKIPPL 0.015 71ESGIRNKSS 0.015 96 AQDSIDPPE 0.015 14 ASPAAAWKC 0.015 82 SQIPVVGVV 0.015139 KSQAASGTL 0.015 147 LSLAFTSWS 0.015 29 RGGLSEIVL 0.013 105 SPDRALKAA0.013 162 SGTWMKLET 0.013 160 LGSGTWMKL 0.013 127 VGPLWEFLL 0.013 146TLSLAFTSW 0.010 88 GVVTEDDEA 0.010 142 AASGTLSLA 0.010 64 GATAEAQES0.010 119 PVLPHTNGV 0.010 46 KIPPLSTPP 0.010 62 EAGATAEAQ 0.010 109ALKAANSWR 0.010 148 SLAFTSWSL 0.010 112 AANSWRNPV 0.010 149 LAFTSWSLG0.010 34 EIVLPIEWQ 0.010 116 WRNPVLPHT 0.010 24 GANILRGGL 0.010 89VVTEDDEAQ 0.010 155 SLGEFLGSG 0.010 120 VLPHTNGVG 0.010 181 KSKHCMFSL0.008 113 ANSWRNPVL 0.005 67 AEAQESGIR 0.005 185 CMFSLISGS 0.005 144SGTLSLAFT 0.005 93 DDEAQDSID 0.005 60 TEEAGATAE 0.005 8 LSVEVLASP 0.003183 KHCMFSLIS 0.003 25 ANILRGGLS 0.003 165 WMKLETIIL 0.003 101 DPPESPDRA0.003 5 SPAAAWKCL 0.003

TABLE IX V1-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ ID NO:3; each start position is specified, the length of peptide is 10 aminoacids, and the end position for each peptide is the start position plusnine. Start Subsequence Score 178 VIELARQLNF 45.000 443 ILDLLQLCRY25.000 294 WLETWLQCRK 18.000 135 SLFPDSLIVK 10.000 200 EIENLPLRLF 9.000356 RIEMYISFGI 4.500 220 ISLATFFFLY 3.750 391 FSFIQSTLGY 3.750 76VTHHEDALTK 2.500 404 LISTFHVLIY 2.500 262 VAITLLSLVY 2.500 275LLAAAYQLYY 2.500 113 LIDVSNNMRI 2.500 351 EEEVWRIEMY 2.500 418AFEEEYYRFY 2.250 123 NQYPESNAEY 1.500 13 LSETCLPNGI 1.350 137 FPDSLIVKGF1.250 427 YTPPNFVLAL 1.250 257 KTLPIVAITL 1.250 271 YLAGLLAAAY 1.000 34GVIGSGDFAK 1.000 321 LCLPMRRSER 1.000 198 AREIENLPLR 0.900 116VSNNMRINQY 0.750 327 RSERYLFLNM 0.675 38 SGDFAKSLTI 0.625 384 NALNWREFSF0.500 218 VAISLATFFF 0.500 274 GLLAAAYQLY 0.500 81 DALTKTNIIF 0.500 322CLPMRRSERY 0.500 73 VVDVTHHEDA 0.500 232 VRDVIHPYAR 0.500 442 VILDLLQLCR0.500 125 YPESNAEYLA 0.450 129 NAEYLASLFP 0.450 21 GINGIKDARK 0.400 2ESISMMGSPK 0.300 66 ASEFFPHVVD 0.270 419 FEEEYYRFTY 0.225 350 NEEEVWRIEM0.225 222 LATFFFLYSF 0.200 56 VVIGSRNPKF 0.200 281 QLYYGTKYRR 0.200 55HVVIGSRNPK 0.200 278 AAYQLYYGTK 0.200 417 RAFEEEYYRF 0.200 216VVVAISLATF 0.200 248 YKIPIEIVNK 0.200 317 VAYSLCLPMR 0.200 17 CLPNGINGIK0.200 244 QSDFYKIPIE 0.150 377 TSIPSVSNAL 0.150 382 VSNALNWREF 0.150 202ENLPLRLFTL 0.125 101 LWDLRHLLVG 0.125 329 ERYLFLNMAY 0.125 15 ETCLPNGING0.125 396 STLGYVALLI 0.125 45 LTIRLIRCGY 0.125 86 TNIIFVAIHR 0.125 32TVGVIGSGDF 0.100 235 VIHPYARNQQ 0.100 410 VLIYGWKRAF 0.100 112ILIDVSNNMR 0.100 166 YICSNNIQAR 0.100 16 TCLPNGINGI 0.100 217 VVAISLATFF0.100 155 QLGPKDASRQ 0.100 344 NIENSWNEEE 0.090 139 DSLIVKGFNV 0.075 405ISTFHVLIYG 0.075 366 MSLGLLSLLA 0.075 11 KSLSETCLPN 0.075 134 ASLFPDSLIV0.075 43 KSLTIRLIRC 0.075 303 KQLGLLSFFF 0.075 361 ISFGIMSLGL 0.075 304QLGLLSFFFA 0.050 107 LLVGKILIDV 0.050 60 SRNPKFASEF 0.050 269 LVYLAGLLAA0.050 434 LALVLPSIVI 0.050 397 TLGYVALLIS 0.050 364 GIMSLGLLSL 0.050 401VALLISTFHV 0.050 147 NVVSAWALQL 0.050 189 PIDLGSLSSA 0.050 264ITLLSLVYLA 0.050 307 LLSFFFAMVH 0.050 310 FFFAMVHVAY 0.050 209FLTWRGPVVV 0.050 194 SLSSAREIEN 0.050 240 ARNQQSDFYK 0.050 298WLQCRKQLGL 0.050 440 SIVILDLLQL 0.050 221 SLATFFFLYS 0.050 436LVLPSIVILD 0.050 406 STFHVLIYGW 0.050

TABLE IX V2-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ ID NO:5; each start position is specified, the length of peptide is 10 aminoacids, and the end position for each peptide is the start position plusnine. Start Subsequence Score 32 RCPPPCPADF 2.000 23 LSLPSSWDYR 1.500 35PPCPADFFLY 0.625 22 CLSLPSSWDY 0.500 33 CPPPCPADFF 0.250 11 LSLSSGFTPF0.150 8 ALSLSLSSGF 0.100 13 LSSGFTPFSC 0.075 2 GSPGLQALSL 0.075 28SWDYRCPPPC 0.050 1 SGSPGLQALS 0.050 36 PCPADFFLYF 0.050 16 GFTPFSCLSL0.025 12 SLSSGFTPFS 0.020 24 SLPSSWDYRC 0.020 20 FSCLSLPSSW 0.015 14SSGFTPFSCL 0.015 9 LSLSLSSGFT 0.015 18 TPFSCLSLPS 0.013 7 QALSLSLSSG0.010 5 GLQALSLSLS 0.010 6 LQALSLSLSS 0.007 10 SLSLSSGFTP 0.005 15SGFTPFSCLS 0.003 3 SPGLQALSLS 0.003 17 FTPFSCLSLP 0.003 34 PPPCPADFFL0.001 4 PGLQALSLSL 0.001 31 YRCPPPCPAD 0.001 21 SCLSLPSSWD 0.001 27SSWDYRCPPP 0.000 25 LPSSWDYRCP 0.000 26 PSSWDYRCPP 0.000 19 PFSCLSLPSS0.000 30 DYRCPPPCPA 0.000 29 WDYRCPPPCP 0.000

TABLE IX V5A-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 1 ENLPLRLFTF 1.250 8 FTFWRGPVVV 0.0503 LPLRLFTFWR 0.013 2 NLPLRLFTFW 0.010 6 RLFTFWRGPV 0.010 7 LFTFWRGPVV0.001 4 PLRLFTFWRG 0.000 10 FWRGPVVVAI 0.000 5 LRLFTFWRGP 0.000 9TFWRGPVVVA 0.000

TABLE IX V5B-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 18 QTELELEFVF 112.500 20 ELELEFVFLL4.500 22 ELEFVFLLTL 4.500 14 FADTQTELEL 2.500 16 DTQTELELEF 1.250 2WREFSFIQIF 0.450 5 FSFIQIFCSF 0.150 12 CSFADTQTEL 0.015 9 QIFCSFADTQ0.010 7 FIQIFCSFAD 0.005 8 IQIFCSFADT 0.003 21 LELEFVFLLT 0.003 4EFSFIQIFCS 0.003 24 EFVFLLTLLL 0.003 3 REFSFIQIFC 0.003 17 TQTELELEFV0.002 11 FCSFADTQTE 0.001 19 TELELEFVFL 0.001 6 SFIQIFCSFA 0.001 10IFCSFADTQT 0.001 23 LEFVFLLTLL 0.001 1 NWREFSFIQI 0.000 15 ADTQTELELE0.000 13 SFADTQTELE 0.000

TABLE IX V6-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ ID NO:13; each start position is specified, the length of peptide is 10 aminoacids, and the end position for each peptide is the start position plusnine. Start Subsequence Score 42 GTIPHVSPER 5.000 2 VLPSIVILGK 1.000 35GLEEGIGGTI 0.900 1 LVLPSIVILG 0.500 12 IILFLPCISR 0.500 6 IVILGKIILF0.500 13 ILFLPCISRK 0.200 15 FLPCISRKLK 0.200 16 LPCISRKLKR 0.125 46HVSPERVTVM 0.100 7 VILGKIILFL 0.050 5 SIVILGKIIL 0.050 18 CISRKLKRIK0.020 19 ISRKLKRIKK 0.015 32 KSQFLEEGIG 0.015 39 GIGGTIPHVS 0.010 43TIPHVSPERV 0.010 11 KIILFLPCIS 0.010 33 SQFLEEGIGG 0.007 38 EGIGGTIPHV0.005 14 LFLPCISRKL 0.005 36 LEEGIGGTIP 0.005 37 EEGIGGTIPH 0.003 3LPSIVILGKI 0.003 44 IPHVSPERVT 0.003 29 GWEKSQFLEE 0.002 4 PSIVILGKII0.002 9 LGKIILGLPC 0.001 23 LKRIKKGWEK 0.001 17 PCISRKLKRI 0.001 10GKIILFLPCI 0.001 26 IKKGWEKSQF 0.001 34 QFLEEGIGGT 0.001 31 EKSQFLEEGI0.001 27 KKGWEKSQFL 0.001 8 ILGKIILFLP 0.001 40 IGGTIPHVSP 0.001 41GGTIPHVSPE 0.000 28 KGWEKSQFLE 0.000 25 RIKKGWEKSQ 0.000 45 PHVSPERVTV0.000 21 RKLKRIKKGW 0.000 20 SRKLKRIKKG 0.000 30 WEKSQFLEEG 0.000 24KRIKKGWEKS 0.000 22 KLKRIKKGWE 0.000

TABLE IX V7A-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 6 LSETFLPNGI 1.350 10 FLPNGINGIK0.200 8 ETFLPNGING 0.125 4 KSLSETFLPN 0.075 5 SLSETFLPNG 0.020 1GSPKSLSETF 0.015 9 TFLPNGINGI 0.005 7 SETFLPNGIN 0.001 2 SPKSLSETFL0.000 3 PKSLSETFLP 0.000

TABLE IX V7B-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 MAYQQSTLGY 2.500 10 STLGYVALLI0.125 9 QSTLGYVALL 0.030 2 FLNMAYQQST 0.010 4 NMAYQQSTLG 0.005 7YQQSTLGYVA 0.003 8 QQSTLGYVAL 0.003 3 LNMAYQQSTL 0.003 6 AYQQSTLGYV0.001 1 LFLNMAYQQS 0.001

TABLE IX V7C-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 100 SIDPPESPDR 100.000 67 TAEAQESGIR9.000 33 LSEIVLPIEW 6.750 131 LWEFLLRLLK 4.500 91 VTEDDEAQDS 2.250 10SVEVLASPAA 1.800 52 STPPPPAMWT 1.250 6 ILDLSVEVLA 1.000 168 KLETIILSKL0.900 103 PPESPDRALK 0.900 127 GVGPLWEFLL 0.500 143 AASGTLSLAF 0.500 13VLASPAAAWK 0.400 51 LSTPPPPAMW 0.300 60 WTEEAGATAE 0.225 157 LGEFLGSGTW0.225 69 EAQESGIRNK 0.200 97 AQDSIDPPES 0.150 70 AQESGIRNKS 0.135 178TQEQKSKHCM 0.135 170 ETIILSKLTQ 0.125 128 VGPLWEFLLR 0.125 37 VLPIEWQQDR0.100 14 LASPAAAWKC 0.100 61 TEEAGATAEA 0.090 39 PIEWQQDRKI 0.090 162GSGTWMKLET 0.075 78 KSSSSSQIPV 0.075 160 FLGSGTWMKL 0.050 22 KCLGANILRG0.050 167 MKLETIILSK 0.050 38 LPIEWQQDRK 0.050 80 SSSSQIPVVG 0.030 79SSSSSQIPVV 0.030 83 SQIPVVGVVT 0.030 144 ASGTLSLAFT 0.030 81 SSSQIPVVGV0.030 146 GTLSLAFTSW 0.025 66 ATAEAQESGI 0.025 152 FTSWSLGEFL 0.025 125TNGVGPLWEF 0.025 92 TEDDEAQDSI 0.025 177 LTQEQKSKHC 0.025 21 WKCLGANILR0.025 106 SPDRALKAAN 0.025 94 DDEAQDSIDP 0.022 12 EVLASPAAAW 0.020 4IVILDLSVEV 0.020 173 ILSKLTQEQK 0.020 47 KIPPLSTPPP 0.020 113 AANSWRNPVL0.020 72 ESGIRNKSSS 0.015 43 QQDRKIPPLS 0.015 15 ASPAAAWKCL 0.015 140KSQAASGTLS 0.015 9 LSVEVLASPA 0.015 82 SSQIPVVGVV 0.015 155 WSLGEFLGSG0.015 105 ESPDRALKAA 0.015 148 LSLAFTSWSL 0.015 124 HTNGVGPLWE 0.013 129GPLWEFLLRL 0.013 31 GGLSEIVLPI 0.013 145 SGTLSLAFTS 0.013 185 HCMFSLISGS0.010 149 SLAFTSWSLG 0.010 65 GATAEAQESG 0.010 112 KAANSWRNPV 0.010 142QAASGTLSLA 0.010 25 GANILRGGLS 0.010 159 EFLGSGTWMK 0.010 23 CLGANILRGG0.010 109 RALKAANSWR 0.010 176 KLTQEQKSKH 0.010 35 EIVLPIEWQQ 0.010 175SKLTQEQKSK 0.010 18 AAAWKCLGAN 0.010 36 IVLPIEWQQD 0.010 5 VILDLSVEVL0.010 172 IILSKLTQEQ 0.010 156 SLGEFLGSGT 0.010 120 PVLPHTNGVG 0.010 147TLSLAFTSWS 0.010 89 GVVTEDDEAQ 0.010 153 TSWSLGEFLG 0.008 2 PSIVILDLSV0.008 141 SQAASGTLSL 0.007 150 LAFTSWSLGE 0.005 17 PAAAWKCLGA 0.005 101IDPPESPDRA 0.005 151 AFTSWSLGEF 0.005 117 WRNPVLPHTN 0.005 42 WQQDRKIPPL0.003 104 PESPDRALKA 0.003 24 LGANILRGGL 0.003 119 NPVLPHTNGV 0.003 118RNPVLPHTNG 0.003 102 DPPESPDRAL 0.003 53 TPPPPAMWTE 0.003 1 LPSIVILDLS0.003

TABLE X V1-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 227 FLYSFVRDV 1789.612 402 ALLISTFHV1492.586 307 LLSFFFAMV 853.681 306 GLLSFFFAM 769.748 100 SLWDLRHLL726.962 333 FLNMAYQQV 479.909 140 SLIVKGFNV 403.402 203 NLPLRLFTL284.974 210 TLWRGPVVV 236.685 65 FASEFFPHV 131.539 135 SLFPDSLIV 105.501274 GLLAAAYQL 79.041 393 FIQSTLGYV 72.344 48 RLIRCGYHV 69.552 365IMSLGLLSL 60.325 5 SMMGSPKSL 57.085 220 ISLATFFFL 53.163 271 YLAGLLAAA52.561 265 TLLSLVYLA 42.278 433 VLALVLPSI 40.792 442 VILDLLQLC 40.518112 ILIDVSNNM 34.627 360 YISFGIMSL 31.077 403 LLISTFHVL 28.290 369GLLSLLAVT 26.001 17 CLPNGINGI 23.995 108 LVGKILIDV 23.795 264 ITLLSLVYL23.608 258 TLPIVAITL 21.362 184 QLNFIPIDL 21.362 313 AMVHVAYSL 15.428410 VLIYGWKRA 14.358 141 LIVKGFNVV 12.665 305 LGLLSFFFA 12.364 44SLTIRLIRC 11.426 436 LVLPSIVIL 11.087 397 TLGYVALLI 10.433 386 LNWREFSFI10.042 180 ELARQLNFI 9.898 254 IVNKTLPIV 9.756 404 LISTFHVLI 9.267 357IEMYISFGI 7.401 441 IVILDLLQL 7.309 261 IVAITLLSL 7.309 209 FTLWRGPVV6.741 368 LGLLSLLAV 6.568 367 SLGLLSLLA 4.968 153 ALQLGPKDA 4.968 146FNVVSAWAL 4.811 389 REFSFIQST 4.686 435 ALVLPSIVI 4.277 187 FIPIDLGSL4.040 374 LAVTSIPSV 3.777 262 VAITLLSLV 3.777 299 LQCRKQLGL 3.682 335NMAYQQVHA 3.588 291 FPPWLETWL 3.528 331 YLFLNMAYQ 3.209 148 VVSAWALQL3.178 166 YICSNNIQA 3.142 353 EVWRIEMYI 3.125 221 SLATFFFLY 3.121 378SIPSVSNAL 2.937 164 QVYICSNNI 2.921 268 SLVYLAGLL 2.777 396 STLGYVALL2.525 434 LALVLPSIV 2.491 304 QLGLLSFFF 2.377 269 LVYLAGLLA 2.365 37GSGDFAKSL 2.173 366 MSLGLLSLL 2.017 267 LSLVYLAGL 2.017 242 NQQSDFYKI2.010 177 QVIELARQL 1.533 224 TFFFLYSFV 1.474 349 WNEEEVWRI 1.418 128SNAEYLASL 1.315 106 HLLVGKILI 1.312 257 KTLPIVAIT 1.264 303 KQLGLLSFF1.238 428 TPPNFVLAL 1.219 34 GVIGSGDFA 1.172 216 VVVAISLAT 1.108 314MVHVAYSLC 1.108 371 LSLLAVTIS 0.985 91 VAIHREHYT 0.968 85 KTNIIFVAI0.964 133 LASLFPDSL 0.939 425 RFYTPPNFV 0.850 250 IPIEIVNKT 0.780 49LIRCGYHVV 0.760 83 LTKTNIIFV 0.727 132 YLASLFPDS 0.651 427 YTPPNFVLA0.603 171 NIQARQQVI 0.588 259 LPIVAITLL 0.545 438 LPSIVILDL 0.545 278AAYQLYYGT 0.497 170 NNIQARQQV 0.454 385 ALNWREFSF 0.432

TABLE X V2-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 5 GLQALSLSL 21.362 10 SLSLSSGFT5.328 17 FTPFSCLSL 1.365 15 SGFTPFSCL 0.980 1 SGSPGLQAL 0.321 14SSGFTPFSC 0.188 8 ALSLSLSSG 0.171 12 SLSSGFTPF 0.142 3 SPGLQALSL 0.13929 WDYRCPPPC 0.102 35 PPCPADFFL 0.098 22 CLSLPSSWD 0.082 37 CPADFFLYF0.079 24 SLPSSWDYR 0.068 25 LPSSWDYRC 0.055 6 LQALSLSLS 0.030 23LSLPSSWDY 0.023 13 LSSGFTPFS 0.017 20 FSCLSLPSS 0.005 7 QALSLSLSS 0.00411 LSLSSGFTP 0.004 27 SSWDYRCPP 0.003 31 YRCPPPCPA 0.003 9 LSLSLSSGF0.003 21 SCLSLPSSW 0.002 18 TPFSCLSLP 0.001 2 GSPGLQALS 0.000 33CPPPCPADF 0.000 16 GFTPFSCLS 0.000 36 PCPADFFLY 0.000 32 RCPPPCPAD 0.0004 PGLQALSLS 0.000 34 PPPCPADFF 0.000 19 PFSCLSLPS 0.000 28 SWDYRCPPP0.000 26 PSSWDYRCP 0.000 30 DYRCPPPCP 0.000

TABLE X V5A-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 7 FTFWRGPVV 6.741 1 NLPLRLFTF 0.9948 TFWRGPVVV 0.164 5 RLFTFWRGP 0.071 2 LPLRLFTFW 0.032 6 LFTFWRGPV 0.0113 PLRLFTFWR 0.003 4 LRLFTFWRG 0.001 9 FWRGPVVVA 0.000

TABLE X V5B-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 20 LELEFVFLL 543.025 6 FIQIFCSFA65.673 24 FVFLLTLLL 31.814 22 LEFVFLLTL 22.835 8 QIFCSFADT 7.203 19ELELEFVFL 1.072 17 QTELELEFV 0.383 10 FCSFADTQT 0.224 4 FSFIQIFCS 0.11021 ELEFVFLLT 0.068 12 SFADTQTEL 0.061 18 TELELEFVF 0.052 16 TQTELELEF0.031 14 ADTQTELEL 0.030 2 REFSFIQIF 0.019 7 IQIFCSFAD 0.015 23EFVFLLTLL 0.003 3 EFSFIQIFC 0.001 1 WREFSFIQI 0.001 11 CSFADTQTE 0.00013 FADTQTELE 0.000 5 SFIQIFCSF 0.000 9 IFCSFADTQ 0.000 15 DTQTELELE0.000

TABLE X V6-HLA-A0201- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 7 ILGKIILFL 459.398 27 KGWEKSQFL91.350 10 KIILFLPCI 43.882 38 GIGGTIPHV 21.996 14 FLPCISRKL 19.653 17CISRKLKRI 3.299 34 FLEEGIGGT 2.689 5 IVILGKIIL 1.303 4 SIVILGKII 0.58843 IPHVSPERV 0.378 1 VLPSIVILG 0.291 46 VSPERVTVM 0.213 45 HVSPERVTV0.207 6 VILGKIILF 0.148 31 KSQFLEEGI 0.117 12 ILFLPCISR 0.094 11IILFLPCIS 0.026 9 GKIILFLPC 0.013 21 KLKRIKKGW 0.009 35 LEEGIGGTI 0.00342 TIPHVSPER 0.002 32 SQFLEEGIG 0.001 20 RKLKRIKKG 0.001 33 QFLEEGIGG0.001 41 GTIPHVSPE 0.000 3 PSIVILGKI 0.000 2 LPSIVILGK 0.000 26KKGWEKSQF 0.000 39 IGGTIPHVS 0.000 24 RIKKGWEKS 0.000 15 LPCISRKLK 0.00013 LFLPCISRK 0.000 40 GGTIPHVSP 0.000 29 WEKSQFLEE 0.000 8 LGKIILFLP0.000 23 KRIKKGWEK 0.000 37 EGIGGTIPH 0.000 30 EKSQFLEEG 0.000 44PHVSPERVT 0.000 36 EEGIGGTIP 0.000 16 PCISRKLKR 0.000 22 LKRIKKGWE 0.00025 IKKGWEKSQ 0.000 18 ISRKLKRIK 0.000 28 GWEKSQFLE 0.000 19 SRKLKRIKK0.000

TABLE X V7A-HLA-A0201- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 FLPNGINGI 110.379 4 SLSETFLPN0.581 6 SETFLPNGI 0.203 3 KSLSETFLP 0.007 2 PKSLSETFL 0.004 5 LSETFLPNG0.000 8 TFLPNGING 0.000 7 ETFLPNGIN 0.000 1 SPKSLSETF 0.000

TABLE X V7B-HLA-A0201- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 6 YQQSTLGYV 53.345 3 NMAYQQSTL15.428 9 STLGYVALL 2.525 1 FLNMAYQQS 0.514 2 LNMAYQQST 0.306 8 QSTLGYVAL0.209 7 QQSTLGYVA 0.207 4 MAYQQSTLG 0.006 5 AYQQSTLGY 0.000

TABLE X V7C-A0201- 9mers-98P4B6 Each peptide is a portion of SEQ ID NO:15; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Start Subsequence Score 4 VILDLSVEV 246.631 148 SLAFTSWSL 160.218129 PLWEFLLRL 139.780 31 GLSEIVLPI 98.381 57 AMWTEEAGA 29.780 2SIVILDLSV 9.563 126 GVGPLWEFL 8.564 5 ILDLSVEVL 6.712 152 TSWSLGEFL3.119 27 ILRGGLSEI 3.100 42 QQDRKIPPL 1.993 168 LETIILSKL 1.624 127VGPLWEFLL 0.375 163 GTWMKLETI 1.355 81 SSQIPVVGV 1.044 165 WMKLETIIL1.018 112 AANSWRNPV 0.966 82 SQIPVVGVV 0.864 134 LLRLLKSQA 0.642 144SGTLSLAFT 0.615 133 FLLRLLKSQ 0.583 39 IEWQQDRKI 0.572 159 FLGSGTWMK0.514 119 PVLPHTNGV 0.495 185 CMFSLISGS 0.458 78 SSSSSQIPV 0.454 79SSSSQIPVV 0.428 83 QIPVVGVVT 0.420 160 LGSGTWMKL 0.403 155 SLGEFLGSG0.347 141 QAASGTLSL 0.297 136 RLLKSQAAS 0.276 52 TPPPPAMWT 0.268 14ASPAAAWKC 0.243 15 SPAAAWKCL 0.237 181 KSKHCMFSL 0.228 88 GVVTEDDEA0.213 22 CLGANILRG 0.171 10 VEVLASPAA 0.164 142 AASGTLSLA 0.159 146TLSLAFTSW 0.142 12 VLASPAAAW 0.127 11 EVLASPAAA 0.121 49 PLSTPPPPA 0.109178 QEQKSKHCM 0.097 59 WTEEAGATA 0.083 17 AAAWKCLGA 0.069 147 LSLAFTSWS0.064 139 KSQAASGTL 0.063 35 IVLPIEWQQ 0.062 29 RGGLSEIVL 0.057 113ANSWRNPVL 0.057 20 WKCLGANIL 0.056 50 LSTPPPPAM 0.055 175 KLTQEQKSK0.052 162 SGTWMKLET 0.049 6 LDLSVEVLA 0.043 36 VLPIEWQQD 0.043 24GANILRGGL 0.039 177 TQEQKSKHC 0.032 105 SPDRALKAA 0.030 171 IILSKLTQE0.030 41 WQQDRKIPP 0.028 9 SVEVLASPA 0.028 182 SKHCMFSLI 0.028 172ILSKLTQEQ 0.025 145 GTLSLAFTS 0.022 138 LKSQAASGT 0.018 154 WSLGEFLGS0.016 76 NKSSSSSQI 0.014 7 DLSVEVLAS 0.013 149 LAFTSWSLG 0.011 116WRNPVLPHT 0.011 104 ESPDRALKA 0.010 66 TAEAQESGI 0.009 125 NGVGPLWEF0.008 169 ETIILSKLT 0.008 167 KLETIILSK 0.008 26 NILRGGLSE 0.008 140SQAASGTLS 0.008 61 EEAGATAEA 0.007 176 LTQEQKSKH 0.007 46 KIPPLSTPP0.007 120 VLPHTNGVG 0.007 166 MKLETIILS 0.006 156 LGEFLGSGT 0.005 158EFLGSGTWM 0.005 131 WEFLLRLLK 0.005 101 DPPESPDRA 0.005 89 VVTEDDEAQ0.004 137 LLKSQAASG 0.004 135 LRLLKSQAA 0.004 108 RALKAANSW 0.004 28LRGGLSEIV 0.003 109 ALKAANSWR 0.003 18 AAWKCLGAN 0.003 91 TEDDEAQDS0.002 164 TWMKLETII 0.002 3 IVILDLSVE 0.002 65 ATAEAQESG 0.002

TABLE XI V1-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 100 SLWDLRHLLV 2366.855 306GLLSFFFAMV 1858.012 82 ALTKTNIIFV 879.833 304 QLGLLSFFFA 301.110 373LLAVTSIPSV 271.948 107 LLVGKILIDV 271.948 132 YLASLFPDSL 182.973 219AISLATFFFL 178.032 367 SLGLLSLLAV 159.970 385 ALNWREFSFI 109.023 298WLQCRKQLGL 98.267 437 VLPSIVILDL 83.527 266 LLSLVYLAGL 83.527 403LLISTFHVLI 67.396 402 ALLISTFHVL 61.573 365 IMSLGLLSLL 60.325 140SLIVKGFNVV 54.181 258 TLPIVAITLL 49.134 433 VLALVLPSIV 48.478 48RLIRCGYHVV 42.774 370 LLSLLAVTSI 40.792 210 TLWRGPVVVA 38.884 263AITLLSLVYL 37.157 432 FVLALVLPSI 35.735 401 VALLISTFHV 35.242 207RLFTLWRGPV 33.455 227 FLYSFVRDVI 30.852 223 ATFFFLYSFV 29.487 65FASEFFPHVV 28.385 364 GIMSLGLLSL 24.997 261 IVAITLLSLV 23.795 435ALVLPSIVIL 20.145 90 FVAIHREHYT 16.497 179 IELARQLNFI 16.141 427YTPPNFVLAL 11.929 67 SEFFPHVVDV 11.509 111 KILIDVSNNM 8.846 305LGLLSFFFAM 8.542 172 IQARQQVIEL 8.469 249 KIPIEIVNKT 8.248 183RQLNFIPIDL 8.014 95 REHYTSLWDL 7.165 440 SIVILDLLQL 6.756 209 FTLWRGPVVV6.741 308 LSFFFAMVHV 6.568 57 VIGSRNPKFA 6.387 419 FEEEYYRFYT 5.579 394IQSTLGYVAL 5.523 269 LVYLAGLLAA 5.439 313 AMVHVAYSLC 5.382 312FAMVHVAYSL 5.050 268 SLVYLAGLLA 4.968 92 AIHREHYTSL 4.406 243 QQSDFYKIPI4.337 257 KTLPIVAITL 3.842 231 FVRDVIHPYA 3.427 314 MVHVAYSLCL 3.178 303KQLGLLSFFF 3.121 221 SLATFFFLYS 2.959 144 KGFNVVSAWA 2.310 286TKYRRFPPWL 1.984 147 NVVSAWALQL 1.869 199 REIENLPLRL 1.703 441IVILDLLQLC 1.700 389 REFSFIQSTL 1.537 226 FFLYSFVRDV 1.437 24 GIKDARKVTV1.372 201 IENLPLRLFT 1.355 393 FIQSTLGYVA 1.288 64 KFASEFFPHV 1.221 152WALQLGPKDA 1.174 345 IENSWNEEEV 1.127 299 LQCRKQLGLL 1.101 163RQVYICSNNI 1.058 428 TPPNFVLALV 1.044 264 ITLLSLVYLA 0.998 113LIDVSNNMRI 0.975 250 IPIEIVNKTL 0.972 43 KSLTIRLIRC 0.966 323 LPMRRSERYL0.965 424 YRFYTPPNFV 0.904 36 IGSGDFAKSL 0.901 361 ISFGIMSLGL 0.877 4ISMMGSPKSL 0.877 336 MAYQQVHANI 0.788 139 DSLIVKGFNV 0.731 12 SLSETCLPNG0.703 275 LLAAAYQLYY 0.697 134 ASLFPDSLIV 0.689 121 RINQYPESNA 0.683 253EIVNKTLPIV 0.676 98 YTSLWDLRHL 0.628 398 LGYVALLIST 0.609 16 TCLPNGINGI0.580 396 STLGYVALLI 0.536 356 RIEMYISFGI 0.532 202 ENLPLRLFTL 0.516 99TSLWDLRHLL 0.516 273 AGLLAAAYQL 0.516 332 LFLNMAYQQV 0.456

TABLE XI V2-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 24 SLPSSWDYRC 4.968 12 SLSSGFTPFS1.557 22 CLSLPSSWDY 0.559 13 LSSGFTPFSC 0.320 14 SSGFTPFSCL 0.265 9LSLSLSSGFT 0.219 5 GLQALSLSLS 0.171 2 GSPGLQALSL 0.139 34 PPPCPADFFL0.098 10 SLSLSSGFTP 0.086 8 ALSLSLSSGF 0.075 16 GFTPFSCLSL 0.015 6LQALSLSLSS 0.013 4 PGLQALSLSL 0.011 7 QALSLSLSSG 0.009 15 SGFTPFSCLS0.007 11 LSLSSGFTPF 0.006 27 SSWDYRCPPP 0.003 23 LSLPSSWDYR 0.003 20FSCLSLPSSW 0.002 17 FTPFSCLSLP 0.002 21 SCLSLPSSWD 0.002 18 TPFSCLSLPS0.002 33 CPPPCPADFF 0.001 3 SPGLQALSLS 0.001 32 RCPPPCPADF 0.000 1SGSPGLQALS 0.000 36 PCPADFFLYF 0.000 29 WDYRCPPPCP 0.000 28 SWDYRCPPPC0.000 35 PPCPADFFLY 0.000 25 LPSSWDYRCP 0.000 31 YRCPPPCPAD 0.000 30DYRCPPPCPA 0.000 19 PFSCLSLPSS 0.000 26 PSSWDYRCPP 0.000

TABLE XI V5A-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 6 RLFTFWRGPV 33.455 8 FTFWRGPVVV6.741 2 NLPLRLFTFW 0.779 3 LPLRLFTFWR 0.074 7 LFTFWRGPVV 0.034 9TFWRGPVVVA 0.027 1 ENLPLRLFTF 0.002 4 PLRLFTFWRG 0.002 10 FWRGPVVVAI0.001 5 LRLFTFWRGP 0.000

TABLE XI V5B-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 17 TQTELELEFV 179.213 19 TELELEFVFL65.849 21 LELEFVFLLT 7.100 23 LEFVFLLTLL 6.009 20 ELELEFVFLL 5.198 8IQIFCSFADT 2.440 3 REFSFIQIFC 1.966 22 ELEFVFLLTL 0.896 14 FADTQTELEL0.546 12 CSFADTQTEL 0.516 6 SFIQIFCSFA 0.072 7 FIQIFCSFAD 0.055 5FSFIQIFCSF 0.016 9 QIFCSFADTQ 0.014 10 IFCSFADTQT 0.009 24 EFVFLLTLLL0.001 1 NWREFSFIQI 0.001 11 FCSFADTQTE 0.000 18 QTELELEFVF 0.000 16DTQTELELEF 0.000 4 EFSFIQIFCS 0.000 15 ADTQTELELE 0.000 13 SFADTQTELE0.000 2 WREFSFIQIF 0.000

TABLE XI V6-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 7 VILGKIILFL 233.719 43 TIPHVSPERV4.686 35 FLEEGIGGTI 1.637 5 SIVILGKIIL 1.204 27 KKGWEKSQFL 0.571 8ILGKIILFLP 0.338 13 ILFLPCISRK 0.216 10 GKIILFLPCI 0.127 1 LVLPSIVILG0.094 38 EGIGGTIPHV 0.078 15 FLPCISRKLK 0.069 28 KGWEKSQFLE 0.067 2VLPSIVILGK 0.058 3 LPSIVILGKI 0.035 33 SQFLEEGIGG 0.028 6 IVILGKIILF0.025 34 QFLEEGIGGT 0.023 14 LFLPCISRKL 0.019 11 KIILFLPCIS 0.015 46HVSPERVTVM 0.014 12 IILFLPCISR 0.013 44 IPHVSPERVT 0.007 39 GIGGTIPHVS0.004 9 LGKIILFLPC 0.004 17 PCISRKLKRI 0.003 22 KLKRIKKGWE 0.001 45PHVSPERVTV 0.001 30 WEKSQFLEEG 0.001 4 PSIVILGKII 0.001 31 EKSQFLEEGI0.001 21 RKLKRIKKGW 0.000 41 GGTIPHVSPE 0.000 42 GTIPHVSPER 0.000 18CISRKLKRIK 0.000 40 IGGTIPHVSP 0.000 16 LPCISRKLKR 0.000 37 EEGIGGTIPH0.000 32 KSQFLEEGIG 0.000 25 RIKKGWEKSQ 0.000 24 KRIKKGWEKS 0.000 23LKRIKKGWEK 0.000 36 LEEGIGGTIP 0.000 19 ISRKLKRIKK 0.000 26 IKKGWEKSQF0.000 20 SRKLKRIKKG 0.000 29 GWEKSQFLEE 0.000

TABLE XI V7A-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 SLSETFLPNG 2.670 9 TFLPNGINGI 0.0622 SPKSLSETFL 0.027 4 KSLSETFLPN 0.012 6 LSETFLPNGI 0.007 10 FLPNGINGIK0.004 8 ETFLPNGING 0.000 1 GSPKSLSETF 0.000 7 SETFLPNGIN 0.000 3PKSLSETFLP 0.000

TABLE XI V7B-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 FLNMAYQQST 34.279 8 QQSTLGYVAL3.249 7 YQQSTLGYVA 0.950 3 LNMAYQQSTL 0.877 10 STLGYVALLI 0.536 9QSTLGYVALL 0.321 4 NMAYQQSTLG 0.054 6 AYQQSTLGYV 0.016 5 MAYQQSTLGY0.006 1 LFLNMAYQQS 0.000

TABLE XI V7C-HLA-A0201- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 160 FLGSGTWMKL 167.054 42 WQQDRKIPPL93.953 134 FLLRLLKSQA 84.555 5 VILDLSVEVL 35.002 156 SLGEFLGSGT 30.55327 NILRGGLSEI 12.208 168 KLETIILSKL 11.006 127 GVGPLWEFLL 10.841 4IVILDLSVEV 10.346 130 PLWEFLLRLL 7.357 148 LSLAFTSWSL 6.579 58AMWTEEAGAT 5.807 129 GPLWEFLLRL 4.510 152 FTSWSLGEFL 3.678 112KAANSWRNPV 3.381 6 ILDLSVEVLA 3.378 141 SQAASGTLSL 2.166 158 GEFLGSGTWM1.966 28 ILRGGLSEIV 1.805 78 KSSSSSQIPV 1.589 147 TLSLAFTSWS 1.557 19AAWKCLGANI 1.203 81 SSSQIPVVGV 1.044 14 LASPAAAWKC 0.880 135 LLRLLKSQAA0.642 126 NGVGPLWEFL 0.639 144 ASGTLSLAFT 0.615 66 ATAEAQESGI 0.594 31GGLSEIVLPI 0.580 52 STPPPPAMWT 0.569 164 GTWMKLETII 0.493 177 LTQEQKSKHC0.481 119 NPVLPHTNGV 0.454 138 LLKSQAASGT 0.443 79 SSSSSQIPVV 0.428 181QKSKHCMFSL 0.396 83 SQIPVVGVVT 0.310 137 RLLKSQAASG 0.276 176 KLTQEQKSKH0.261 169 LETIILSKLT 0.246 15 ASPAAAWKCL 0.237 9 LSVEVLASPA 0.226 11VEVLASPAAA 0.164 92 TEDDEAQDSI 0.163 142 QAASGTLSLA 0.159 13 VLASPAAAWK0.139 149 SLAFTSWSLG 0.127 113 AANSWRNPVL 0.122 50 PLSTPPPPAM 0.109 163SGTWMKLETI 0.077 122 LPHTNGVGPL 0.071 32 GLSEIVLPIE 0.058 132 WEFLLRLLKS0.057 82 SSQIPVVGVV 0.056 162 GSGTWMKLET 0.049 23 CLGANILRGG 0.034 178TQEQKSKHCM 0.032 24 LGANILRGGL 0.031 10 SVEVLASPAA 0.028 88 VGVVTEDDEA0.027 37 VLPIEWQQDR 0.025 121 VLPHTNGVGP 0.025 153 TSWSLGEFLG 0.023 105ESPDRALKAA 0.023 166 WMKLETIILS 0.020 110 ALKAANSWRN 0.020 182KSKHCMFSLI 0.016 22 KCLGANILRG 0.014 36 IVLPIEWQQD 0.014 172 IILSKLTQEQ0.013 173 ILSKLTQEQK 0.012 2 PSIVILDLSV 0.010 155 WSLGEFLGSG 0.009 115NSWRNPVLPH 0.009 90 VVTEDDEAQD 0.009 102 DPPESPDRAL 0.009 125 TNGVGPLWEF0.008 146 GTLSLAFTSW 0.007 47 KIPPLSTPPP 0.007 139 LKSQAASGTL 0.007 61TEEAGATAEA 0.006 101 IDPPESPDRA 0.006 57 PAMWTEEAGA 0.006 59 MWTEEAGATA0.005 171 TIILSKLTQE 0.005 84 QIPVVGVVTE 0.005 165 TWMKLETIIL 0.005 109RALKAANSWR 0.004 97 AQDSIDPPES 0.003 43 QQDRKIPPLS 0.003 145 SGTLSLAFTS0.003 49 PPLSTPPPPA 0.003 8 DLSVEVLASP 0.003 76 RNKSSSSSQI 0.002 104PESPDRALKA 0.002 29 LRGGLSEIVL 0.002 3 SIVILDLSVE 0.002 12 EVLASPAAAW0.002 34 SEIVLPIEWQ 0.002 140 KSQAASGTLS 0.002

TABLE XII V1-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 221 SLATFFFLY 108.000 306 GLLSFFFAM24.300 294 WLETWLQCR 18.000 281 QLYYGTKYR 10.000 249 KIPIEIVNK 9.000 103DLRHLLVGK 9.000 274 GLLAAAYQL 8.100 443 ILDLLQLCR 8.000 223 ATFFFLYSF6.750 304 QLGLLSFFF 6.000 155 QLGPKDASR 6.000 385 ALNWREFSF 6.000 35VIGSGDFAK 6.000 409 HVLIYGWKR 5.400 56 VVIGSRNPK 4.500 313 AMVHVAYSL4.050 82 ALTKTNIIF 4.000 322 CLPMRRSER 4.000 275 LLAAAYQLY 4.000 135SLFPDSLIV 3.000 100 SLWDLRHLL 3.000 21 GINGIKDAR 2.700 403 LLISTFHVL2.700 265 TLLSLVYLA 2.700 435 ALVLPSIVI 2.700 203 NLPLRLFTL 2.700 205PLRLFTLWR 2.400 3 SISMMGSPK 2.000 258 TLPIVAITL 1.800 184 QLNFIPIDL1.800 397 TLGYVALLI 1.800 365 IMSLGLLSL 1.800 307 LLSFFFAMV 1.800 87NIIFVAIHR 1.800 106 HLLVGKILI 1.800 433 VLALVLPSI 1.350 191 DLGSLSSAR1.200 210 TLWRGPVVV 1.000 140 SLIVKGFNV 0.900 17 CLPNGINGI 0.900 231FVRDVIHPY 0.900 48 RLIRCGYHV 0.900 402 ALLISTFHV 0.900 227 FLYSFVRDV0.900 417 RAFEEEYYR 0.900 263 AITLLSLVY 0.800 5 SMMGSPKSL 0.675 369GLLSLLAVT 0.675 396 STLGYVALL 0.608 303 KQLGLLSFF 0.608 44 SLTIRLIRC0.600 381 SVSNALNWR 0.600 46 TIRLIRCGY 0.600 219 AISLATFFF 0.600 280YQLYYGTKY 0.540 411 LIYGWKRAF 0.450 271 YLAGLLAAA 0.450 112 ILIDVSNNM0.450 85 KTNIIFVAI 0.405 90 FVAIHREHY 0.400 367 SLGLLSLLA 0.400 113LIDVSNNMR 0.400 148 VVSAWALQL 0.360 175 RQQVIELAR 0.360 217 VVAISLATF0.300 164 QVYICSNNI 0.300 400 YVALLISTF 0.300 43 KSLTIRLIR 0.270 441IVILDLLQL 0.270 268 SLVYLAGLL 0.270 180 ELARQLNFI 0.270 353 EVWRIEMYI0.270 358 EMYISFGIM 0.270 276 LAAAYQLYY 0.240 436 LVLPSIVIL 0.203 335NMAYQQVHA 0.200 57 VIGSRNPKF 0.200 269 LVYLAGLLA 0.200 333 FLNMAYQQV0.200 261 IVAITLLSL 0.180 225 FFFLYSFVR 0.180 360 YISFGIMSL 0.180 437VLPSIVILD 0.180 404 LISTFHVLI 0.180 242 NQQSDFYKI 0.162 257 KTLPIVAIT0.152 331 YLFLNMAYQ 0.150 410 VLIYGWKRA 0.150 34 GVIGSGDFA 0.135 18LPNGINGIK 0.135 107 LLVGKILID 0.135 241 RNQQSDFYK 0.120 405 ISTFHVLIY0.120 132 YLASLFPDS 0.120 428 TPPNFVLAL 0.108 153 ALQLGPKDA 0.100 108LVGKILIDV 0.090 378 SIPSVSNAL 0.090 141 LIVKGFNVV 0.090 282 LYYGTKYRR0.090

TABLE XII V2-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 12 SLSSGFTPF 6.000 24 SLPSSWDYR4.000 5 GLQALSLSL 3.600 37 CPADFFLYF 0.360 23 LSLPSSWDY 0.135 17FTPFSCLSL 0.060 36 PCPADFFLY 0.036 8 ALSLSLSSG 0.030 22 CLSLPSSWD 0.03010 SLSLSSGFT 0.030 33 CPPPCPADF 0.030 25 LPSSWDYRC 0.018 9 LSLSLSSGF0.015 15 SGFTPFSCL 0.013 3 SPGLQALSL 0.012 34 PPPCPADFF 0.003 14SSGFTPFSC 0.003 21 SCLSLPSSW 0.003 35 PPCPADFFL 0.003 6 LQALSLSLS 0.00218 TPFSCLSLP 0.002 27 SSWDYRCPP 0.002 1 SGSPGLQAL 0.001 7 QALSLSLSS0.001 29 WDYRCPPPC 0.001 13 LSSGFTPFS 0.001 2 GSPGLQALS 0.001 16GFTPFSCLS 0.001 31 YRCPPPCPA 0.000 11 LSLSSGFTP 0.000 32 RCPPPCPAD 0.00020 FSCLSLPSS 0.000 28 SWDYRCPPP 0.000 4 PGLQALSLS 0.000 30 DYRCPPPCP0.000 19 PFSCLSLPS 0.000 26 PSSWDYRCP 0.000

TABLE XII V5A-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 NLPLRLFTF 9.000 3 PLRLFTFWR 3.6007 FTFWRGPVV 0.050 5 RLFTFWRGP 0.030 2 LPLRLFTFW 0.009 9 FWRGPVVVA 0.0018 TFWRGPVVV 0.001 4 LRLFTFWRG 0.000 6 LFTFWRGPV 0.000

TABLE XII V5B-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 24 FVFLLTLLL 0.600 19 ELELEFVFL0.540 21 ELEFVFLLT 0.270 16 TQTELELEF 0.180 8 QIFCSFADT 0.150 2REFSFIQIF 0.135 20 LELEFVFLL 0.109 22 LEFVFLLTL 0.081 6 FIQIFCSFA 0.06018 TELELEFVF 0.041 17 QTELELEFV 0.015 5 SFIQIFCSF 0.013 4 FSFIQIFCS0.005 1 WREFSFIQI 0.004 7 IQIFCSFAD 0.003 14 ADTQTELEL 0.001 10FCSFADTQT 0.001 12 SFADTQTEL 0.001 11 CSFADTQTE 0.001 15 DTQTELELE 0.00023 EFVFLLTLL 0.000 13 FADTQTELE 0.000 3 EFSFIQIFC 0.000 9 IFCSFADTQ0.000

TABLE XII V6-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 12 ILFLPCISR 60.000 7 ILGKIILFL2.700 6 VILGKIILF 1.350 10 KIILFLPCI 1.215 2 LPSIVILGK 0.900 42TIPHVSPER 0.600 21 KLKRIKKGW 0.450 23 KRIKKGWEK 0.270 5 IVILGKIIL 0.1801 VLPSIVILG 0.180 38 GIGGTIPHV 0.135 15 LPCISRKLK 0.100 14 FLPCISRKL0.090 13 LFLPCISRK 0.068 34 FLEEGIGGT 0.068 17 CISRKLKRI 0.045 4SIVILGKII 0.045 19 SRKLKRIKK 0.040 45 HVSPERVTV 0.030 41 GTIPHVSPE 0.02027 KGWEKSQFL 0.014 16 PCISRKLKR 0.012 18 ISRKLKRIK 0.010 31 KSQFLEEGI0.009 26 KKGWEKSQF 0.006 11 IILFLPCIS 0.006 9 GKIILFLPC 0.005 46VSPERVTVM 0.005 24 RIKKGWEKS 0.004 43 IPHVSPERV 0.002 35 LEEGIGGTI 0.00132 SQFLEEGIG 0.001 29 WEKSQFLEE 0.000 3 PSIVILGKI 0.000 37 EGIGGTIPH0.000 28 GWEKSQFLE 0.000 8 LGKIILFLP 0.000 33 QFLEEGIGG 0.000 40GGTIPHVSP 0.000 39 IGGTIPHVS 0.000 25 IKKGWEKSQ 0.000 30 EKSQFLEEG 0.00020 RKLKRIKKG 0.000 36 EEGIGGTIP 0.000 22 LKRIKKGWE 0.000 44 PHVSPERVT0.000

TABLE XII V7A-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 FLPNGINGI 0.900 4 SLSETFLPN 0.1801 SPKSLSETF 0.020 6 SETFLPNGI 0.002 3 KSLSETFLP 0.001 7 ETFLPNGIN 0.0015 LSETFLPNG 0.000 8 TFLPNGING 0.000 2 PKSLSETFL 0.000

TABLE XII V7B-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 STLGYVALL 0.608 3 NMAYQQSTL 0.6001 FLNMAYQQS 0.040 7 QQSTLGYVA 0.018 5 AYQQSTLGY 0.008 8 QSTLGYVAL 0.0036 YQQSTLGYV 0.003 4 MAYQQSTLG 0.001 2 LNMAYQQST 0.001

TABLE XII V7C-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 167 KLETIILSK 270.000 159 FLGSGTWMK60.000 175 KLTQEQKSK 30.000 31 GLSEIVLPI 24.300 129 PLWEFLLRL 4.050 109ALKAANSWR 4.000 148 SLAFTSWSL 1.800 5 ILDLSVEVL 1.800 27 ILRGGLSEI 1.350165 WMKLETIIL 1.200 128 GPLWEFLLR 1.080 57 AMWTEEAGA 1.000 163 GTWMKLETI0.675 146 TLSLAFTSW 0.600 131 WEFLLRLLK 0.600 21 KCLGANILR 0.540 12VLASPAAAW 0.300 185 CMFSLISGS 0.300 13 LASPAAAWK 0.300 37 LPIEWQQDR0.270 126 GVGPLWEFL 0.270 38 PIEWQQDRK 0.200 134 LLRLLKSQA 0.200 173LSKLTQEQK 0.100 88 GVVTEDDEA 0.090 69 AQESGIRNK 0.090 7 DLSVEVLAS 0.0722 SIVILDLSV 0.060 136 RLLKSQAAS 0.060 22 CLGANILRG 0.060 151 FTSWSLGEF0.045 155 SLGEFLGSG 0.041 181 KSKHCMFSL 0.041 125 NGVGPLWEF 0.030 49PLSTPPPPA 0.030 4 VILDLSVEV 0.030 145 GTLSLAFTS 0.027 42 QQDRKIPPL 0.027123 HTNGVGPLW 0.022 51 STPPPPAMW 0.022 133 FLLRLLKSQ 0.022 35 IVLPIEWQQ0.020 36 VLPIEWQQD 0.020 172 ILSKLTQEQ 0.020 143 ASGTLSLAF 0.020 9SVEVLASPA 0.020 137 LLKSQAASG 0.020 82 SQIPVVGVV 0.018 179 EQKSKHCMF0.018 59 WTEEAGATA 0.015 83 QIPVVGVVT 0.015 152 TSWSLGEFL 0.015 176LTQEQKSKH 0.015 73 GIRNKSSSS 0.012 141 QAASGTLSL 0.012 46 KIPPLSTPP0.009 11 EVLASPAAA 0.009 103 PESPDRALK 0.009 100 IDPPESPDR 0.006 112AANSWRNPV 0.006 170 TIILSKLTQ 0.006 120 VLPHTNGVG 0.006 66 TAEAQESGI0.006 26 NILRGGLSE 0.006 127 VGPLWEFLL 0.005 24 GANILRGGL 0.005 142AASGTLSLA 0.005 81 SSQIPVVGV 0.005 52 TPPPPAMWT 0.005 3 IVILDLSVE 0.005171 IILSKLTQE 0.005 119 PVLPHTNGV 0.005 99 SIDPPESPD 0.005 168 LETIILSKL0.004 17 AAAWKCLGA 0.004 67 AEAQESGIR 0.004 108 RALKAANSW 0.003 15SPAAAWKCL 0.003 86 VVGVVTEDD 0.003 177 TQEQKSKHC 0.003 14 ASPAAAWKC0.003 89 VVTEDDEAQ 0.003 154 WSLGEFLGS 0.003 139 KSQAASGTL 0.003 157GEFLGSGTW 0.003 50 LSTPPPPAM 0.002 34 EIVLPIEWQ 0.002 85 PVVGVVTED 0.00278 SSSSSQIPV 0.002 182 SKHCMFSLI 0.002 160 LGSGTWMKL 0.002 115 SWRNPVLPH0.002 33 SEIVLPIEW 0.002 79 SSSSQIPVV 0.002 105 SPDRALKAA 0.002 65ATAEAQESG 0.002 64 GATAEAQES 0.001 29 RGGLSEIVL 0.001 113 ANSWRNPVL0.001 140 SQAASGTLS 0.001

TABLE XIII V1-HLA-A3- 10-98P4B6 Each peptide is a portion of SEQ ID NO:3; each start position is specified, the length of peptide is 10 aminoacids, and the end position for each peptide is the start position plusnine. Start Subsequence Score 135 SLFPDSLIVK 450.000 281 QLYYGTKYRR60.000 34 GVIGSGDFAK 40.500 275 LLAAAYQLYY 24.000 294 WLETWLQCRK 20.000274 GLLAAAYQLY 18.000 17 CLPNGINGIK 9.000 21 GINGIKDARK 9.000 306GLLSFFFAMV 8.100 271 YLAGLLAAAY 6.000 112 ILIDVSNNMR 6.000 443ILDLLQLCRY 6.000 227 FLYSFVRDVI 4.500 210 TLWRGPVVVA 4.500 322CLPMRRSERY 4.000 55 HVVIGSRNPK 3.000 402 ALLISTFHVL 2.700 266 LLSLVYLAGL2.700 403 LLISTFHVLI 2.700 437 VLPSIVILDL 2.700 404 LISTFHVLIY 2.400 107LLVGKILIDV 2.025 100 SLWDLRHLLV 2.000 76 VTHHEDALTK 2.000 370 LLSLLAVTSI1.800 132 YLASLFPDSL 1.800 304 QLGLLSFFFA 1.800 385 ALNWREFSFI 1.800 435ALVLPSIVIL 1.350 303 KQLGLLSFFF 1.215 307 LLSFFFAMVH 1.200 442VILDLLQLCR 1.200 298 WLQCRKQLGL 1.200 365 IMSLGLLSLL 0.900 410VLIYGWKRAF 0.900 140 SLIVKGFNVV 0.900 207 RLFTLWRGPV 0.900 258TLPIVAITLL 0.900 123 NQYPESNAEY 0.900 278 AAYQLYYGTK 0.900 364GIMSLGLLSL 0.810 427 YTPPNFVLAL 0.810 220 ISLATFFFLY 0.810 221SLATFFFLYS 0.720 257 KTLPIVAITL 0.608 333 FLNMAYQQVH 0.600 268SLVYLAGLLA 0.600 324 PMRRSERYLF 0.600 82 ALTKTNIIFV 0.600 367 SLGLLSLLAV0.600 203 NLPLRLFTLW 0.600 166 YICSNNIQAR 0.600 219 AISLATFFFL 0.540 147NVVSAWALQL 0.540 150 SAWALQLGPK 0.450 56 VVIGSRNPKF 0.450 417 RAFEEEYYRF0.450 45 LTIRLIRCGY 0.450 216 VVVAISLATF 0.450 178 VIELARQLNF 0.400 204LPLRLFTLWR 0.360 358 EMYISFGIMS 0.360 314 MVHVAYSLCL 0.360 48 RLIRCGYHVV0.300 317 VAYSLCLPMR 0.300 331 YLFLNMAYQQ 0.300 313 AMVHVAYSLC 0.300 373LLAVTSIPSV 0.300 269 LVYLAGLLAA 0.300 440 SIVILDLLQL 0.270 222LATFFFLYSF 0.270 154 LQLGPKDASR 0.270 85 KTNIIFVAIH 0.270 356 RIEMYISFGI0.270 406 STFHVLIYGW 0.225 396 STLGYVALLI 0.203 432 FVLALVLPSI 0.203 217VVAISLATFF 0.200 433 VLALVLPSIV 0.200 391 FSFIQSTLGY 0.200 369GLLSLLAVTS 0.180 224 TFFFLYSFVR 0.180 49 LIRCGYHVVI 0.180 103 DLRHLLVGKI0.162 111 KILIDVSNNM 0.135 249 KIPIEIVNKT 0.135 264 ITLLSLVYLA 0.135 5SMMGSPKSLS 0.135 113 LIDVSNNMRI 0.120 262 VAITLLSLVY 0.120 372SLLAVTSIPS 0.120 397 TLGYVALLIS 0.120 157 GPKDASRQVY 0.120 172IQARQQVIEL 0.108 243 QQSDFYKIPI 0.108 347 NSWNEEEVWR 0.100 39 GDFAKSLTIR0.090 218 VAISLATFFF 0.090 384 NALNWREFSF 0.090 285 GTKYRRFPPW 0.090

TABLE XIII V2-HLA-A3- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 22 CLSLPSSWDY 12.000 8 ALSLSLSSGF2.000 24 SLPSSWDYRC 1.800 5 GLQALSLSLS 0.180 12 SLSSGFTPFS 0.120 10SLSLSSGFTP 0.060 35 PPCPADFFLY 0.054 11 LSLSSGFTPF 0.045 23 LSLPSSWDYR0.045 33 CPPPCPADFF 0.045 36 PCPADFFLYF 0.036 32 RCPPPCPADF 0.030 2GSPGLQALSL 0.027 14 SSGFTPFSCL 0.013 16 GFTPFSCLSL 0.005 13 LSSGFTPFSC0.005 18 TPFSCLSLPS 0.004 6 LQALSLSLSS 0.002 34 PPPCPADFFL 0.002 17FTPFSCLSLP 0.002 20 FSCLSLPSSW 0.001 3 SPGLQALSLS 0.001 15 SGFTPFSCLS0.001 27 SSWDYRCPPP 0.001 21 SCLSLPSSWD 0.000 7 QALSLSLSSG 0.000 9LSLSLSSGFT 0.000 28 SWDYRCPPPC 0.000 4 PGLQALSLSL 0.000 29 WDYRCPPPCP0.000 30 DYRCPPPCPA 0.000 1 SGSPGLQALS 0.000 31 YRCPPPCPAD 0.000 26PSSWDYRCPP 0.000 25 LPSSWDYRCP 0.000 19 PFSCLSLPSS 0.000

TABLE XIII V5A-HLA-A3- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 6 RLFTFWRGPV 0.900 2 NLPLRLFTFW 0.6003 LPLRLFTFWR 0.540 8 FTFWRGPVVV 0.050 4 PLRLFTFWRG 0.018 1 ENLPLRLFTF0.012 9 TFWRGPVVVA 0.005 10 FWRGPVVVAI 0.004 7 LFTFWRGPVV 0.000 5LRLFTFWRGP 0.000

TABLE XIII V5B-HLA-A3- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 20 ELELEFVFLL 4.860 22 ELEFVFLLTL1.620 18 QTELELEFVF 0.300 5 FSFIQIFCSF 0.225 16 DTQTELELEF 0.060 9QIFCSFADTQ 0.030 12 CSFADTQTEL 0.015 8 IQIFCSFADT 0.013 23 LEFVFLLTLL0.013 17 TQTELELEFV 0.013 19 TELELEFVFL 0.012 14 FADTQTELEL 0.012 2WREFSFIQIF 0.009 3 REFSFIQIFC 0.009 21 LELEFVFLLT 0.006 7 FIQIFCSFAD0.006 1 NWREFSFIQI 0.005 6 SFIQIFCSFA 0.001 24 EFVFLLTLLL 0.001 11FCSFADTQTE 0.000 10 IFCSFADTQT 0.000 4 EFSFIQIFCS 0.000 15 ADTQTELELE0.000 13 SFADTQTELE 0.000

TABLE XIII V6-HLA-A3- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 13 ILFLPCISRK 150.000 2 VLPSIVILGK90.000 15 FLPCISRKLK 10.000 42 GTIPHVSPER 2.025 12 IILFLPCISR 1.800 6IVILGKIILF 0.900 7 VILGKIILFL 0.608 35 FLEEGIGGTI 0.405 19 ISRKLKRIKK0.200 18 CISRKLKRIK 0.200 5 SIVILGKIIL 0.180 8 ILGKIILFLP 0.135 46HVSPERVTVM 0.090 16 LPCISRKLKR 0.080 23 LKRIKKGWEK 0.060 1 LVLPSIVILG0.041 39 GIGGTIPHVS 0.027 43 TIPHVSPERV 0.020 22 KLKRIKKGWE 0.018 11KIILFLPCIS 0.018 10 GKIILFLPCI 0.012 33 SQFLEEGIGG 0.006 3 LPSIVILGKI0.004 26 IKKGWEKSQF 0.003 25 RIKKGWEKSQ 0.003 27 KKGWEKSQFL 0.002 28KGWEKSQFLE 0.001 9 LGKIILFLPC 0.001 17 PCISRKLKRI 0.001 29 GWEKSQFLEE0.000 37 EEGIGGTIPH 0.000 30 WEKSQFLEEG 0.000 21 RKLKRIKKGW 0.000 4PSIVILGKII 0.000 38 EGIGGTIPHV 0.000 14 LFLPCISRKL 0.000 41 GGTIPHVSPE0.000 24 KRIKKGWEKS 0.000 31 EKSQFLEEGI 0.000 44 IPHVSPERVT 0.000 34QFLEEGIGGT 0.000 32 KSQFLEEGIG 0.000 36 LEEGIGGTIP 0.000 45 PHVSPERVTV0.000 40 IGGTIPHVSP 0.000 20 SRKLKRIKKG 0.000

TABLE XIII V7A-HLA-A3- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 10 FLPNGINGIK 9.000 5 SLSETFLPNG0.135 1 GSPKSLSETF 0.030 2 SPKSLSETFL 0.006 6 LSETFLPNGI 0.003 8ETFLPNGING 0.003 4 KSLSETFLPN 0.003 9 TFLPNGINGI 0.002 7 SETFLPNGIN0.000 3 PKSLSETFLP 0.000

TABLE XIII V7B-HLA-A3- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 MAYQQSTLGY 0.400 2 FLNMAYQQST 0.30010 STLGYVALLI 0.203 9 QSTLGYVALL 0.027 4 NMAYQQSTLG 0.020 7 YQQSTLGYVA0.018 8 QQSTLGYVAL 0.018 3 LNMAYQQSTL 0.002 6 AYQQSTLGYV 0.000 1LFLNMAYQQS 0.000

TABLE XIII V7C-HLA-A3- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 13 VLASPAAAWK 20.000 173 ILSKLTQEQK20.000 37 VLPIEWQQDR 12.000 168 KLETIILSKL 4.050 127 GVGPLWEFLL 2.430160 FLGSGTWMKL 1.200 100 SIDPPESPDR 0.600 176 KLTQEQKSKH 0.600 38LPIEWQQDRK 0.450 164 GTWMKLETII 0.450 134 FLLRLLKSQA 0.300 6 ILDLSVEVLA0.300 28 ILRGGLSEIV 0.300 5 VILDLSVEVL 0.270 129 GPLWEFLLRL 0.243 167MKLETIILSK 0.203 32 GLSEIVLPIE 0.203 135 LLRLLKSQAA 0.200 156 SLGEFLGSGT0.150 58 AMWTEEAGAT 0.150 146 GTLSLAFTSW 0.135 27 NILRGGLSEI 0.135 166WMKLETIILS 0.120 147 TLSLAFTSWS 0.120 138 LLKSQAASGT 0.100 130PLWEFLLRLL 0.068 143 AASGTLSLAF 0.060 110 ALKAANSWRN 0.060 109RALKAANSWR 0.060 66 ATAEAQESGI 0.045 115 NSWRNPVLPH 0.045 159 EFLGSGTWMK0.041 131 LWEFLLRLLK 0.040 141 SQAASGTLSL 0.036 152 FTSWSLGEFL 0.030 50PLSTPPPPAM 0.030 137 RLLKSQAASG 0.030 4 IVILDLSVEV 0.030 19 AAWKCLGANI0.030 125 TNGVGPLWEF 0.027 42 WQQDRKIPPL 0.027 182 KSKHCMFSLI 0.027 31GGLSEIVLPI 0.024 128 VGPLWEFLLR 0.024 52 STPPPPAMWT 0.022 103 PPESPDRALK0.020 10 SVEVLASPAA 0.020 149 SLAFTSWSLG 0.020 121 VLPHTNGVGP 0.020 112KAANSWRNPV 0.018 175 SKLTQEQKSK 0.015 148 LSLAFTSWSL 0.013 12 EVLASPAAAW0.013 8 DLSVEVLASP 0.013 69 EAQESGIRNK 0.013 74 GIRNKSSSSS 0.012 67TAEAQESGIR 0.012 83 SQIPVVGVVT 0.010 89 GVVTEDDEAQ 0.009 47 KIPPLSTPPP0.009 14 LASPAAAWKC 0.009 158 GEFLGSGTWM 0.009 21 WKCLGANILR 0.008 177LTQEQKSKHC 0.007 179 QEQKSKHCMF 0.006 113 AANSWRNPVL 0.006 84 QIPVVGVVTE0.006 178 TQEQKSKHCM 0.006 150 LAFTSWSLGE 0.006 78 KSSSSSQIPV 0.006 122LPHTNGVGPL 0.005 3 SIVILDLSVE 0.005 36 IVLPIEWQQD 0.005 23 CLGANILRGG0.005 171 TIILSKLTQE 0.005 81 SSSQIPVVGV 0.005 22 KCLGANILRG 0.004 35EIVLPIEWQQ 0.004 119 NPVLPHTNGV 0.003 162 GSGTWMKLET 0.003 142QAASGTLSLA 0.003 124 HTNGVGPLWE 0.003 90 VVTEDDEAQD 0.003 172 IILSKLTQEQ0.003 181 QKSKHCMFSL 0.003 9 LSVEVLASPA 0.002 51 LSTPPPPAMW 0.002 87VVGVVTEDDE 0.002 33 LSEIVLPIEW 0.002 91 VTEDDEAQDS 0.002 165 TWMKLETIIL0.002 29 LRGGLSEIVL 0.002 70 AQESGIRNKS 0.002 132 WEFLLRLLKS 0.002 43QQDRKIPPLS 0.002 92 TEDDEAQDSI 0.002 79 SSSSSQIPVV 0.002 60 WTEEAGATAE0.002 153 TSWSLGEFLG 0.002 15 ASPAAAWKCL 0.002

TABLE XIV V1-HLA-A1101- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 56 VVIGSRNPK 3.000 409 HVLIYGWKR1.200 249 KIPIEIVNK 1.200 35 VIGSGDFAK 1.200 175 RQQVIELAR 0.720 417RAFEEEYYR 0.480 3 SISMMGSPK 0.400 279 AYQLYYGTK 0.400 136 LFPDSLIVK0.400 381 SVSNALNWR 0.400 241 RNQQSDFYK 0.360 282 LYYGTKYRR 0.320 225FFFLYSFVR 0.240 21 GINGIKDAR 0.240 53 GYHVVIGSR 0.240 87 NIIFVAIHR 0.24018 LPNGINGIK 0.200 443 ILDLLQLCR 0.160 103 DLRHLLVGK 0.120 34 GVIGSGDFA0.090 322 CLPMRRSER 0.080 113 LIDVSNNMR 0.080 155 QLGPKDASR 0.080 318AYSLCLPMR 0.080 269 LVYLAGLLA 0.080 281 QLYYGTKYR 0.080 294 WLETWLQCR0.080 97 HYTSLWDLR 0.080 295 LETWLQCRK 0.060 441 IVILDLLQL 0.060 306GLLSFFFAM 0.054 199 REIENLPLR 0.054 22 INGIKDARK 0.040 148 VVSAWALQL0.040 77 THHEDALTK 0.040 108 LVGKILIDV 0.040 223 ATFFFLYSF 0.040 261IVAITLLSL 0.040 167 ICSNNIQAR 0.040 164 QVYICSNNI 0.040 43 KSLTIRLIR0.036 233 RDVIHPYAR 0.036 48 RLIRCGYHV 0.036 274 GLLAAAYQL 0.036 330RYLFLNMAY 0.036 408 FHVLIYGWK 0.030 85 KTNIIFVAI 0.030 436 LVLPSIVIL0.030 303 KQLGLLSFF 0.027 353 EVWRIEMYI 0.024 191 DLGSLSSAR 0.024 254IVNKTLPIV 0.020 90 FVAIHREHY 0.020 151 AWALQLGPK 0.020 83 LTKTNIIFV0.020 98 YTSLWDLRH 0.020 231 FVRDVIHPY 0.020 400 YVALLISTF 0.020 217VVAISLATF 0.020 402 ALLISTFHV 0.018 64 KFASEFFPH 0.018 140 SLIVKGFNV0.018 214 GPVVVAISL 0.018 135 SLFPDSLIV 0.016 205 PLRLFTLWR 0.016 209FTLWRGPVV 0.015 264 ITLLSLVYL 0.015 396 STLGYVALL 0.015 319 YSLCLPMRR0.012 394 IQSTLGYVA 0.012 30 KVTVGVIGS 0.012 270 VYLAGLLAA 0.012 203NLPLRLFTL 0.012 425 RFYTPPNFV 0.012 242 NQQSDFYKI 0.012 287 KYRRFPPWL0.012 453 ALVLPSIVI 0.012 265 TLLSLVYLA 0.012 299 LQCRKQLGL 0.012 313AMVHVAYSL 0.012 40 DFAKSLTIR 0.012 106 HLLVGKILI 0.012 426 FYTPPNFVL0.012 385 ALNWREFSF 0.012 219 AISLATFFF 0.012 304 QLGLLSFFF 0.012 221SLATFFFLY 0.012 427 YTPPNFVLA 0.010 285 GTKYRRFPP 0.009 280 YQLYYGTKY0.009 397 TLGYVALLI 0.008 367 SLGLLSLLA 0.008 166 YICSNNIQA 0.008 258TLPIVAITL 0.008 317 VAYSLCLPM 0.008 100 SLWDLRHLL 0.008 210 TLWRGPVVV0.008 365 IMSLGLLSL 0.008 263 AITLLSLVY 0.008 360 YISFGIMSL 0.008

TABLE XIV V2-HLA-A1101- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 24 SLPSSWDYR 0.080 5 GLQALSLSL 0.02417 FTPFSCLSL 0.020 3 SPGLQALSL 0.004 12 SLSSGFTPF 0.004 37 CPADFFLYF0.004 21 SCLSLPSSW 0.003 33 CPPPCPADF 0.002 23 LSLPSSWDY 0.001 6LQALSLSLS 0.001 16 GFTPFSCLS 0.001 32 RCPPPCPAD 0.001 36 PCPADFFLY 0.00135 PPCPADFFL 0.001 7 QALSLSLSS 0.001 10 SLSLSSGFT 0.000 15 SGFTPFSCL0.000 22 CLSLPSSWD 0.000 8 ALSLSLSSG 0.000 18 TPFSCLSLP 0.000 25LPSSWDYRC 0.000 9 LSLSLSSGF 0.000 1 SGSPGLQAL 0.000 31 YRCPPPCPA 0.00034 PPPCPADFF 0.000 30 DYRCPPPCP 0.000 11 LSLSSGFTP 0.000 14 SSGFTPFSC0.000 2 GSPGLQALS 0.000 19 PFSCLSLPS 0.000 29 WDYRCPPPC 0.000 27SSWDYRCPP 0.000 13 LSSGFTPFS 0.000 20 FSCLSLPSS 0.000 28 SWDYRCPPP 0.0004 PGLQALSLS 0.000 26 PSSWDYRCP 0.000

TABLE XIV V5A-HLA-A1101- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 3 PLRLFTFWR 0.024 7 FTFWRGPVV 0.0201 NLPLRLFTF 0.012 8 TFWRGPVVV 0.004 2 LPLRLFTFW 0.003 6 LFTFWRGPV 0.0025 RLFTFWRGP 0.000 9 FWRGPVVVA 0.000 4 LRLFTFWRG 0.000

TABLE XIV V5B-HLA-A11- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 24 FVFLLTLLL 0.080 16 TQTELELEF0.012 17 QTELELEFV 0.010 6 FIQIFCSFA 0.004 2 REFSFIQIF 0.004 5 SFIQIFCSF0.003 7 IQIFCSFAD 0.003 18 TELELEFVF 0.003 20 LELEFVFLL 0.003 22LEFVFLLTL 0.002 12 SFADTQTEL 0.002 19 ELELEFVFL 0.001 23 EFVFLLTLL 0.0018 QIFCSFADT 0.001 14 ADTQTELEL 0.000 1 WREFSFIQI 0.000 15 DTQTELELE0.000 21 ELEFVFLLT 0.000 9 IFCSFADTQ 0.000 13 FADTQTELE 0.000 10FCSFADTQT 0.000 4 FSFIQIFCS 0.000 3 EFSFIQIFC 0.000 11 CSFADTQTE 0.000

TABLE XIV V6-HLA-A1101- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 LPSIVILGK 0.400 12 ILFLPCISR 0.32013 LFLPCISRK 0.300 23 KRIKKGWEK 0.180 15 LPCISRKLK 0.100 42 TIPHVSPER0.080 5 IVILGKIIL 0.060 19 SRKLKRIKK 0.040 45 HVSPERVTV 0.020 10KIILFLPCI 0.018 16 PCISRKLKR 0.012 6 VILGKIILF 0.012 38 GIGGTIPHV 0.0127 ILGKIILFL 0.008 21 KLKRIKKGW 0.006 41 GTIPHVSPE 0.005 4 SIVILGKII0.003 18 ISRKLKRIK 0.002 17 CISRKLKRI 0.002 43 IPHVSPERV 0.002 32SQFLEEGIG 0.001 24 RIKKGWEKS 0.001 27 KGWEKSQFL 0.001 1 VLPSIVILG 0.00126 KKGWEKSQF 0.001 11 IILFLPCIS 0.001 33 QFLEEGIGG 0.001 31 KSQFLEEGI0.001 35 LEEGIGGTI 0.001 14 FLPCISRKL 0.000 34 FLEEGIGGT 0.000 46VSPERVTVM 0.000 9 GKIILFLPC 0.000 28 GWEKSQFLE 0.000 37 EGIGGTIPH 0.00029 WEKSQFLEE 0.000 8 LGKIILFLP 0.000 40 GGTIPHVSP 0.000 20 RKLKRIKKG0.000 3 PSIVILGKI 0.000 22 LKRIKKGWE 0.000 39 IGGTIPHVS 0.000 36EEGIGGTIP 0.000 25 IKKGWEKSQ 0.000 30 EKSQFLEEG 0.000 44 PHVSPERVT 0.000

TABLE XIV V7A-HLA-A1101- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 FLPNGINGI 0.004 1 SPKSLSETF 0.0024 SLSETFLPN 0.001 7 ETFLPNGIN 0.001 8 TFLPNGING 0.001 6 SETFLPNGI 0.0013 KSLSETFLP 0.000 2 PKSLSETFL 0.000 5 LSETFLPNG 0.000

TABLE XIV V7B-HLA-A1101- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 STLGYVALL 0.015 7 QQSTLGYVA 0.0125 AYQQSTLGY 0.008 6 YQQSTLGYV 0.006 3 NMAYQQSTL 0.004 4 MAYQQSTLG 0.0001 FLNMAYQQS 0.000 8 QSTLGYVAL 0.000 2 LNMAYQQST 0.000

TABLE XIV V7C-HLA-A1101- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 167 KLETIILSK 2.400 159 FLGSGTWMK0.800 175 KLTQEQKSK 0.600 21 KCLGANILR 0.360 128 GPLWEFLLR 0.360 131WEFLLRLLK 0.240 13 LASPAAAWK 0.200 88 GVVTEDDEA 0.090 109 ALKAANSWR0.080 69 AQESGIRNK 0.060 163 GTWMKLETI 0.060 37 LPIEWQQDR 0.060 126GVGPLWEFL 0.060 38 PIEWQQDRK 0.040 31 GLSEIVLPI 0.024 173 LSKLTQEQK0.020 9 SVEVLASPA 0.020 145 GTLSLAFTS 0.013 2 SIVILDLSV 0.012 67AEAQESGIR 0.012 151 FTSWSLGEF 0.010 176 LTQEQKSKH 0.010 51 STPPPPAMW0.010 59 WTEEAGATA 0.010 123 HTNGVGPLW 0.010 11 EVLASPAAA 0.009 82SQIPVVGVV 0.009 108 RALKAANSW 0.009 57 AMWTEEAGA 0.008 165 WMKLETIIL0.008 148 SLAFTSWSL 0.008 4 VILDLSVEV 0.006 103 PESPDRALK 0.006 42QQDRKIPPL 0.006 24 GANILRGGL 0.006 35 IVLPIEWQQ 0.006 5 ILDLSVEVL 0.004134 LLRLLKSQA 0.004 100 IDPPESPDR 0.004 141 QAASGTLSL 0.004 27 ILRGGLSEI0.004 146 TLSLAFTSW 0.004 12 VLASPAAAW 0.004 17 AAAWKCLGA 0.004 157GEFLGSGTW 0.004 3 IVILDLSVE 0.003 119 PVLPHTNGV 0.003 89 VVTEDDEAQ 0.00266 TAEAQESGI 0.002 86 VVGVVTEDD 0.002 142 AASGTLSLA 0.002 112 AANSWRNPV0.002 181 KSKHCMFSL 0.002 136 RLLKSQAAS 0.002 179 EQKSKHCMF 0.002 33SEIVLPIEW 0.002 129 PLWEFLLRL 0.002 170 TIILSKLTQ 0.001 73 GIRNKSSSS0.001 29 RGGLSEIVL 0.001 46 KIPPLSTPP 0.001 41 WQQDRKIPP 0.001 26NILRGGLSE 0.001 105 SPDRALKAA 0.001 65 ATAEAQESG 0.001 15 SPAAAWKCL0.001 90 VTEDDEAQD 0.001 158 EFLGSGTWM 0.001 10 VEVLASPAA 0.001 22CLGANILRG 0.001 185 CMFSLISGS 0.001 184 HCMFSLISG 0.001 127 VGPLWEFLL0.001 139 KSQAASGTL 0.001 125 NGVGPLWEF 0.001 64 GATAEAQES 0.001 140SQAASGTLS 0.001 171 IILSKLTQE 0.001 96 AQDSIDPPE 0.001 168 LETIILSKL0.001 178 QEQKSKHCM 0.001 101 DPPESPDRA 0.001 164 TWMKLETII 0.000 49PLSTPPPPA 0.000 18 AAWKCLGAN 0.000 143 ASGTLSLAF 0.000 150 AFTSWSLGE0.000 36 VLPIEWQQD 0.000 83 QIPVVGVVT 0.000 160 LGSGTWMKL 0.000 52TPPPPAMWT 0.000 172 ILSKLTQEQ 0.000 115 SWRNPVLPH 0.000 99 SIDPPESPD0.000 149 LAFTSWSLG 0.000 113 ANSWRNPVL 0.000 155 SLGEFLGSG 0.000 137LLKSQAASG 0.000 120 VLPHTNGVG 0.000 78 SSSSSQIPV 0.000

TABLE XV V1-HLA-A1101- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 34 GVIGSGDFAK 27.000 55 HVVIGSRNPK3.000 76 VTHHEDALTK 2.000 135 SLFPDSLIVK 1.600 21 GINGIKDARK 1.200 294WLETWLQCRK 0.400 278 AAYQLYYGTK 0.400 150 SAWALQLGPK 0.400 17 CLPNGINGIK0.400 281 QLYYGTKYRR 0.320 442 VILDLLQLCR 0.240 224 TFFFLYSFVR 0.240 407TFHVLIYGWK 0.200 154 LQLGPKDASR 0.180 318 AYSLCLPMRR 0.160 204LPLRLFTLWR 0.120 112 ILIDVSNNMR 0.120 280 YQLYYGTKYR 0.090 257KTLPIVAITL 0.090 303 KQLGLLSFFF 0.081 166 YICSNNIQAR 0.080 269LVYLAGLLAA 0.080 317 VAYSLCLPMR 0.080 240 ARNQQSDFYK 0.060 321LCLPMRRSER 0.060 147 NVVSAWALQL 0.060 183 RQLNFIPIDL 0.054 364GIMSLGLLSL 0.048 406 STFHVLIYGW 0.040 254 IVNKTLPIVA 0.040 314MVHVAYSLCL 0.040 316 HVAYSLCLPM 0.040 356 RIEMYISFGI 0.036 425RFYTPPNFVL 0.036 102 WDLRHLLVGK 0.030 248 YKIPIEIVNK 0.030 56 VVIGSRNPKF0.030 285 GTKYRRFPPW 0.030 216 VVVAISLATF 0.030 83 LTKTNIIFVA 0.030 85KTNIIFVAIH 0.030 396 STLGYVALLI 0.030 432 FVLALVLPSI 0.030 264ITLLSLVYLA 0.030 163 RQVYICSNNI 0.027 416 KRAFEEEYYR 0.024 86 TNIIFVAIHR0.024 39 GDFAKSLTIR 0.024 417 RAFEEEYYRF 0.024 207 RLFTLWRGPV 0.024 217VVAISLATFF 0.020 223 ATFFFLYSFV 0.020 400 YVALLISTFH 0.020 261IVAITLLSLV 0.020 32 TVGVIGSGDF 0.020 142 IVKGFNVVSA 0.020 231 FVRDVIHPYA0.020 73 VVDVTHHEDA 0.020 340 QVHANIENSW 0.020 427 YTPPNFVLAL 0.020 339GYVALLISTF 0.018 111 KILIDVSNNM 0.018 274 GLLAAAYQLY 0.018 48 RLIRCGYHVV0.018 306 GLLSFFFAMV 0.018 100 SLWDLRHLLV 0.016 45 LTIRLIRCGY 0.015 209FTLWRGPVVV 0.015 409 HVLIYGWKRA 0.015 408 FHVLIYGWKR 0.012 243QQSDFYKIPI 0.012 440 SIVILDLLQL 0.012 24 GIKDARKVTV 0.012 304 QLGLLSFFFA0.012 145 GFNVVSAWAL 0.012 359 MYISFGIMSL 0.012 172 IQARQQVIEL 0.012 121RINQYPESNA 0.012 123 NQYPESNAEY 0.012 165 VYICSNNIQA 0.012 107LLVGKILIDV 0.012 219 AISLATFFFL 0.012 268 SLVYLAGLLA 0.012 376VTSIPSVSNA 0.010 2 ESISMMGSPK 0.009 401 VALLISTFHV 0.009 214 GPVVVAISLA0.009 218 VAISLATFFF 0.009 384 NALNWREFSF 0.009 367 SLGLLSLLAV 0.008 307LLSFFFAMVH 0.008 437 VLPSIVILDL 0.008 227 FLYSFVRDVI 0.008 42 AKSLTIRLIR0.008 113 LIDVSNNMRI 0.008 210 TLWRGPVVVA 0.008 178 VIELARQLNF 0.008 298WLQCRKQLGL 0.008 404 LISTFHVLIY 0.008 82 ALTKTNIIFV 0.008

TABLE XV 2V-HLA-A1101- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 16 GFTPFSCLSL 0.012 22 CLSLPSSWDY0.008 23 LSLPSSWDYR 0.006 32 RCPPPCPADF 0.006 8 ALSLSLSSGF 0.004 33CPPPCPADFF 0.002 6 LQALSLSLSS 0.001 2 GSPGLQALSL 0.001 5 GLQALSLSLS0.001 10 SLSLSSGFTP 0.001 30 DYRCPPPCPA 0.001 17 FTPFSCLSLP 0.001 18TPFSCLSLPS 0.001 24 SLPSSWDYRC 0.001 35 PPCPADFFLY 0.001 34 PPPCPADFFL0.001 36 PCPADFFLYF 0.000 12 SLSSGFTPFS 0.000 11 LSLSSGFTPF 0.000 21SCLSLPSSWD 0.000 7 QALSLSLSSG 0.000 3 SPGLQALSLS 0.000 20 FSCLSLPSSW0.000 14 SSGFTPFSCL 0.000 4 PGLQALSLSL 0.000 13 LSSGFTPFSC 0.000 29WDYRCPPPCP 0.000 27 SSWDYRCPPP 0.000 15 SGFTPFSCLS 0.000 9 LSLSLSSGFT0.000 31 YRCPPPCPAD 0.000 19 PFSCLSLPSS 0.000 25 LPSSWDYRCP 0.000 28SWDYRCPPPC 0.000 1 SGSPGLQALS 0.000 26 PSSWDYRCPP 0.000

TABLE XV V5A-HLA-A1101- 10-mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 LPLRLFTFWR 0.180 6 RLFTFWRGPV 0.0248 FTFWRGPVVV 0.020 9 TFWRGPVVVA 0.004 2 NLPLRLFTFW 0.004 7 LFTFWRGPVV0.002 1 ENLPLRLFTF 0.001 10 FWRGPVVVAI 0.000 4 PLRLFTFWRG 0.000 5LRLFTFWRGP 0.000

TABLE XV V5B-HLA-A1101- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 18 QTELELEFVF 0.030 16 DTQTELELEF0.006 17 TQTELELEFV 0.006 14 FADTQTELEL 0.004 20 ELELEFVFLL 0.004 6SFIQIFCSFA 0.003 22 ELEFVFLLTL 0.002 24 EFVFLLTLLL 0.002 7 FIQIFCSFAD0.001 23 LEFVFLLTLL 0.001 8 IQIFCSFADT 0.001 19 TELELEFVFL 0.001 9QIFCSFADTQ 0.001 3 REFSFIQIFC 0.001 1 NWREFSFIQI 0.000 12 CSFADTQTEL0.000 5 FSFIQIFCSF 0.000 13 SFADTQTELE 0.000 2 WREFSFIQIF 0.000 11FCSFADTQTE 0.000 10 IFCSFADTQT 0.000 4 EFSFIQIFCS 0.000 21 LELEFVFLLT0.000 15 ADTQTELELE 0.000

TABLE XV V6-HLA-A1101- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 42 GTIPHVSPER 0.900 2 VLPSIVILGK0.800 13 ILFLPCISRK 0.800 12 IILFLPCISR 0.240 15 FLPCISRKLK 0.200 16LPCISRKLKR 0.080 6 IVILGKIILF 0.060 19 ISRKLKRIKK 0.040 18 CISRKLKRIK0.040 23 LKRIKKGWEK 0.040 46 HVSPERVTVM 0.020 5 SIVILGKIIL 0.012 7VILGKIILFL 0.012 1 LVLPSIVILG 0.006 35 FLEEGIGGTI 0.004 43 TIPHVSPERV0.004 33 SQFLEEGIGG 0.002 3 LPSIVILGKI 0.002 11 KIILFLPCIS 0.002 39GIGGTIPHVS 0.001 8 ILGKIILFLP 0.001 22 KLKRIKKGWE 0.001 10 GKIILFLPCI0.001 25 RIKKGWEKSQ 0.001 27 KKGWEKSQFL 0.001 21 RKLKRIKKGW 0.000 28KGWEKSQFLE 0.000 37 EEGIGGTIPH 0.000 14 LFLPCISRKL 0.000 34 QFLEEGIGGT0.000 26 IKKGWEKSQF 0.000 17 PCISRKLKRI 0.000 29 GWEKSQFLEE 0.000 24KRIKKGWEKS 0.000 38 EGIGGTIPHV 0.000 41 GGTIPHVSPE 0.000 32 KSQFLEEGIG0.000 36 LEEGIGGTIP 0.000 31 EKSQFLEEGI 0.000 30 WEKSQFLEEG 0.000 9LGKIILFLPC 0.000 45 PHVSPERVTV 0.000 44 IPHVSPERVT 0.000 40 IGGTIPHVSP0.000 4 PSIVILGKII 0.000 20 SRKLKRIKKG 0.000

TABLE XV V7A-HLA-A1101- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 10 FLPNGINGIK 0.400 9 TFLPNGINGI0.003 2 SPKSLSETFL 0.002 8 ETFLPNGING 0.001 1 GSPKSLSETF 0.001 5SLSETFLPNG 0.000 6 LSETFLPNGI 0.000 4 KSLSETFLPN 0.000 7 SETFLPNGIN0.000 3 PKSLSETFLP 0.000

TABLE XV V7B-A1101- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 10 STLGYVALLI 0.030 7 YQQSTLGYVA0.012 5 MAYQQSTLGY 0.008 8 QQSTLGYVAL 0.006 6 AYQQSTLGYV 0.004 3LNMAYQQSTL 0.001 2 FLNMAYQQST 0.000 4 NMAYQQSTLG 0.000 1 LFLNMAYQQS0.000 9 QSTLGYVALL 0.000

TABLE XV V7C-A1101- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 173 ILSKLTQEQK 0.400 13 VLASPAAAWK0.400 38 LPIEWQQDRK 0.300 109 RALKAANSWR 0.180 127 GVGPLWEFLL 0.180 159EFLGSGTWMK 0.180 100 SIDPPESPDR 0.080 37 VLPIEWQQDR 0.080 167 MKLETIILSK0.060 164 GTWMKLETII 0.060 146 GTLSLAFTSW 0.045 131 LWEFLLRLLK 0.040 67TAEAQESGIR 0.040 4 IVILDLSVEV 0.030 103 PPESPDRALK 0.020 10 SVEVLASPAA0.020 129 GPLWEFLLRL 0.018 175 SKLTQEQKSK 0.015 176 KLTQEQKSKH 0.012 141SQAASGTLSL 0.012 168 KLETIILSKL 0.012 66 ATAEAQESGI 0.010 152 FTSWSLGEFL0.010 12 EVLASPAAAW 0.009 89 GVVTEDDEAQ 0.009 160 FLGSGTWMKL 0.008 21WKCLGANILR 0.008 128 VGPLWEFLLR 0.008 5 VILDLSVEVL 0.006 112 KAANSWRNPV0.006 134 FLLRLLKSQA 0.006 69 EAQESGIRNK 0.006 27 NILRGGLSEI 0.006 178TQEQKSKHCM 0.006 42 WQQDRKIPPL 0.006 6 ILDLSVEVLA 0.004 135 LLRLLKSQAA0.004 143 AASGTLSLAF 0.004 19 AAWKCLGANI 0.004 28 ILRGGLSEIV 0.004 158GEFLGSGTWM 0.004 36 IVLPIEWQQD 0.003 119 NPVLPHTNGV 0.003 124 HTNGVGPLWE0.002 113 AANSWRNPVL 0.002 122 LPHTNGVGPL 0.002 52 STPPPPAMWT 0.002 90VVTEDDEAQD 0.002 142 QAASGTLSLA 0.002 87 VVGVVTEDDE 0.002 151 AFTSWSLGEF0.002 31 GGLSEIVLPI 0.002 137 RLLKSQAASG 0.002 22 KCLGANILRG 0.002 74GIRNKSSSSS 0.001 47 KIPPLSTPPP 0.001 32 GLSEIVLPIE 0.001 76 RNKSSSSSQI0.001 78 KSSSSSQIPV 0.001 60 WTEEAGATAE 0.001 91 VTEDDEAQDS 0.001 83SQIPVVGVVT 0.001 170 ETIILSKLTQ 0.001 11 VEVLASPAAA 0.001 165 TWMKLETIIL0.001 125 TNGVGPLWEF 0.001 110 ALKAANSWRN 0.001 166 WMKLETIILS 0.001 115NSWRNPVLPH 0.001 150 LAFTSWSLGE 0.001 58 AMWTEEAGAT 0.001 3 SIVILDLSVE0.001 182 KSKHCMFSLI 0.001 171 TIILSKLTQE 0.001 70 AQESGIRNKS 0.001 181QKSKHCMFSL 0.001 172 IILSKLTQEQ 0.001 148 LSLAFTSWSL 0.001 65 GATAEAQESG0.001 25 GANILRGGLS 0.001 97 AQDSIDPPES 0.001 43 QQDRKIPPLS 0.001 92TEDDEAQDSI 0.001 61 TEEAGATAEA 0.001 179 QEQKSKHCMF 0.001 177 LTQEQKSKHC0.001 147 TLSLAFTSWS 0.000 121 VLPHTNGVGP 0.000 17 PAAAWKCLGA 0.000 138LLKSQAASGT 0.000 29 LRGGLSEIVL 0.000 53 TPPPPAMWTE 0.000 14 LASPAAAWKC0.000 84 QIPVVGVVTE 0.000 50 PLSTPPPPAM 0.000 185 HCMFSLISGS 0.000 57PAMWTEEAGA 0.000 149 SLAFTSWSLG 0.000 33 LSEIVLPIEW 0.000 156 SLGEFLGSGT0.000

TABLE XVI V1-HLA-A24- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 287 KYRRFPPWL 400.000 426 FYTPPNFVL240.000 337 AYQQVHANI 105.000 283 YYGTKYRRF 100.000 228 LYSFVRDVI 70.000390 EFSFIQSTL 28.000 362 SFGIMSLGL 20.000 418 AFEEEYYRF 18.000 330RYLFLNMAY 18.000 378 SIPSVSNAL 10.080 124 QYPESNAEY 9.900 399 GYVALLIST9.000 177 QVIELARQL 8.640 184 QLNFIPIDL 8.400 258 TLPIVAITL 8.400 313AMVHVAYSL 8.400 214 GPVVVAISL 8.400 246 DFYKIPIEI 7.700 270 VYLAGLLAA7.500 359 MYISFGIMS 7.500 268 SLVYLAGLL 7.200 291 FPPWLETWL 7.200 366MSLGLLSLL 7.200 220 ISLATFFFL 7.200 403 LLISTFHVL 7.200 303 KQLGLLSFF7.200 436 LVLPSIVIL 7.200 200 EIENLPLRL 7.200 61 RNPKFASEF 6.600 428TPPNFVLAL 6.000 274 GLLAAAYQL 6.000 125 YPESNAEYL 6.000 363 FGIMSLGLL6.000 264 ITLLSLVYL 6.000 396 STLGYVALL 6.000 297 TWLQCRKQL 6.000 259LPIVAITLL 6.000 5 SMMGSPKSL 6.000 203 NLPLRLFTL 6.000 441 IVILDLLQL6.000 187 FIPIDLGSL 6.000 146 FNVVSAWAL 6.000 267 LSLVYLAGL 6.000 99TSLWDLRHL 6.000 100 SLWDLRHLL 5.760 438 LPSIVILDL 5.600 85 KTNIIFVAI5.040 247 FYKIPIEIV 5.000 423 YYRFYTPPN 5.000 128 SNAEYLASL 4.800 41FAKSLTIRL 4.800 37 GSGDFAKSL 4.800 173 QARQQVIEL 4.400 300 QCRKQLGLL4.000 75 DVTHHEDAL 4.000 395 QSTLGYVAL 4.000 299 LQCRKQLGL 4.000 133LASLFPDSL 4.000 365 IMSLGLLSL 4.000 148 VVSAWALQL 4.000 360 YISFGIMSL4.000 261 IVAITLLSL 4.000 196 SSAREIENL 4.000 129 NAEYLASLF 3.600 218VAISLATFF 3.600 385 ALNWREFSF 3.000 33 VGVIGSGDF 3.000 400 YVALLISTF2.400 304 QLGLLSFFF 2.400 383 SNALNWREF 2.200 57 VIGSRNPKF 2.200 223ATFFFLYSF 2.000 411 LIYGWKRAF 2.000 219 AISLATFFF 2.000 62 NPKFASEFF2.000 82 ALTKTNIIF 2.000 239 YARNQQSDF 2.000 217 VVAISLATF 2.000 242NQQSDFYKI 1.980 81 DALTKTNII 1.800 17 CLPNGINGI 1.800 349 WNEEEVWRI1.800 171 NIQARQQVI 1.800 290 RFPPWLETW 1.800 105 RHLLVGKIL 1.680 193GSLSSAREI 1.650 112 ILIDVSNNM 1.512 435 ALVLPSIVI 1.500 106 HLLVGKILI1.500 134 ASLFPDSLI 1.500 253 EIVNKTLPI 1.500 371 LSLLAVTSI 1.500 353EVWRIEMYI 1.400 397 TLGYVALLI 1.400 433 VLALVLPSI 1.400 186 NFIPIDLGS1.260 164 QVYICSNNI 1.200 180 ELARQLNFI 1.200 425 RFYTPPNFV 1.200 386LNWREFSFI 1.200

TABLE XVI V2-HLA-A24- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 5 GLQALSLSL 7.200 17 FTPFSCLSL 6.0001 SGSPGLQAL 5.760 15 SGFTPFSCL 4.800 3 SPGLQALSL 4.000 33 CPPPCPADF3.600 9 LSLSLSSGF 3.600 37 CPADFFLYF 2.880 12 SLSSGFTPF 2.400 16GFTPFSCLS 0.600 30 DYRCPPPCP 0.500 35 PPCPADFFL 0.480 34 PPPCPADFF 0.30023 LSLPSSWDY 0.180 2 GSPGLQALS 0.180 21 SCLSLPSSW 0.180 7 QALSLSLSS0.180 14 SSGFTPFSC 0.100 10 SLSLSSGFT 0.100 6 LQALSLSLS 0.100 25LPSSWDYRC 0.100 13 LSSGFTPFS 0.100 20 FSCLSLPSS 0.100 19 PFSCLSLPS 0.06032 RCPPPCPAD 0.036 36 PCPADFFLY 0.018 24 SLPSSWDYR 0.015 4 PGLQALSLS0.015 11 LSLSSGFTP 0.015 27 SSWDYRCPP 0.012 31 YRCPPPCPA 0.012 18TPFSCLSLP 0.010 29 WDYRCPPPC 0.010 8 ALSLSLSSG 0.010 28 SWDYRCPPP 0.01022 CLSLPSSWD 0.010 26 PSSWDYRCP 0.001

TABLE XVI V5A-HLA-A24- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 NLPLRLFTF 3.000 8 TFWRGPVVV 0.5006 LFTFWRGPV 0.500 2 LPLRLFTFW 0.216 7 FTFWRGPVV 0.100 9 FWRGPVVVA 0.1005 RLFTFWRGP 0.020 4 LRLFTFWRG 0.002 3 PLRLFTFWR 0.001

TABLE XVI V5B-HLA-A24- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 23 EFVFLLTLL 36.000 12 SFADTQTEL26.400 5 SFIQIFCSF 25.200 19 ELELEFVFL 7.200 24 FVFLLTLLL 4.800 16TQTELELEF 3.168 20 LELEFVFLL 0.720 3 EFSFIQIFC 0.700 2 REFSFIQIF 0.48014 ADTQTELEL 0.440 18 TELELEFVF 0.432 22 LEFVFLLTL 0.400 21 ELEFVFLLT0.252 1 WREFSFIQI 0.180 6 FIQIFCSFA 0.150 17 QTELELEFV 0.150 8 QIFCSFADT0.120 10 FCSFADTQT 0.100 4 FSFIQIFCS 0.100 9 IFCSFADTQ 0.050 7 IQIFCSFAD0.015 15 DTQTELELE 0.015 11 CSFADTQTE 0.012 13 FADTQTELE 0.010

TABLE XVI V6-HLA-A24- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 27 KGWEKSQFL 11.520 14 FLPCISRKL9.240 5 IVILGKIIL 6.000 7 ILGKIILFL 5.600 31 KSQFLEEGI 3.600 10KIILFLPCI 3.000 6 VILGKIILF 3.000 4 SIVILGKII 1.800 17 CISRKLKRI 1.00046 VSPERVTVM 0.900 26 KKGWEKSQF 0.400 21 KLKRIKKGW 0.280 3 PSIVILGKI0.231 24 RIKKGWEKS 0.220 35 LEEGIGGTI 0.210 34 FLEEGIGGT 0.180 11IILFLPCIS 0.180 39 IGGTIPHVS 0.140 45 HVSPERVTV 0.120 38 GIGGTIPHV 0.10043 IPHVSPERV 0.100 33 QFLEEGIGG 0.090 13 LFLPCISRK 0.090 42 TIPHVSPER0.023 9 GKIILFLPC 0.022 1 VLPSIVILG 0.021 41 GTIPHVSPE 0.018 28GWEKSQFLE 0.015 37 EGIGGTIPH 0.015 2 LPSIVILGK 0.014 8 LGKIILFLP 0.01418 ISRKLKRIK 0.012 32 SQFLEEGIG 0.010 40 GGTIPHVSP 0.010 15 LPCISRKLK0.010 12 ILFLPCISR 0.010 23 KRIKKGWEK 0.003 20 RKLKRIKKG 0.003 16PCISRKLKR 0.002 44 PHVSPERVT 0.002 29 WEKSQFLEE 0.001 19 SRKLKRIKK 0.00130 EKSQFLEEG 0.001 22 LKRIKKGWE 0.001 25 IKKGWEKSQ 0.001 36 EEGIGGTIP0.001

TABLE XVI V7A-HLA-A24- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 SPKSLSETF 2.400 9 FLPNGINGI 1.8004 SLSETFLPN 0.144 6 SETFLPNGI 0.144 7 ETFLPNGIN 0.100 8 TFLPNGING 0.0902 PKSLSETFL 0.040 3 KSLSETFLP 0.030 5 LSETFLPNG 0.015

TABLE XVI V7B-HLA-A24- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 5 AYQQSTLGY 7.500 9 STLGYVALL 6.0008 QSTLGYVAL 4.000 3 NMAYQQSTL 4.000 1 FLNMAYQQS 0.180 2 LNMAYQQST 0.1806 YQQSTLGYV 0.150 7 QQSTLGYVA 0.120 4 MAYQQSTLG 0.010

TABLE XVI V7C-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 139 KSQAASGTL 12.000 29 RGGLSEIVL8.000 181 KSKHCMFSL 8.000 130 LWEFLLRLL 7.200 24 GANILRGGL 7.200 127VGPLWEFLL 6.000 126 GVGPLWEFL 5.760 152 TSWSLGEFL 4.800 160 LGSGTWMKL4.400 148 SLAFTSWSL 4.000 42 QQDRKIPPL 4.000 15 SPAAAWKCL 4.000 141QAASGTLSL 4.000 5 ILDLSVEVL 4.000 165 WMKLETIIL 4.000 113 ANSWRNPVL4.000 158 EFLGSGTWM 3.750 125 NGVGPLWEF 3.300 143 ASGTLSLAF 2.400 151FTSWSLGEF 2.200 179 EQKSKHCMF 2.000 164 TWMKLETII 1.800 31 GLSEIVLPI1.680 66 TAEAQESGI 1.500 19 AWKCLGANI 1.200 27 ILRGGLSEI 1.100 163GTWMKLETI 1.000 132 EFLLRLLKS 0.825 168 LETIILSKL 0.616 102 PPESPDRAL0.600 50 LSTPPPPAM 0.600 129 PLWEFLLRL 0.480 20 WKCLGANIL 0.480 108RALKAANSW 0.360 117 RNPVLPHTN 0.360 136 RLLKSQAAS 0.300 82 SQIPVVGVV0.252 4 VILDLSVEV 0.238 123 HTNGVGPLW 0.210 83 QIPVVGVVT 0.210 104ESPDRALKA 0.198 51 STPPPPAMW 0.180 145 GTLSLAFTS 0.180 154 WSLGEFLGS0.180 68 EAQESGIRN 0.180 9 SVEVLASPA 0.180 59 WTEEAGATA 0.180 156LGEFLGSGT 0.180 52 TPPPPAMWT 0.180 112 AANSWRNPV 0.180 101 DPPESPDRA0.180 2 SIVILDLSV 0.180 169 ETIILSKLT 0.180 88 GVVTEDDEA 0.165 14ASPAAAWKC 0.165 25 ANILRGGLS 0.150 72 SGIRNKSSS 0.150 11 EVLASPAAA 0.15081 SSQIPVVGV 0.150 177 TQEQKSKHC 0.150 147 LSLAFTSWS 0.150 64 GATAEAQES0.132 134 LLRLLKSQA 0.120 146 TLSLAFTSW 0.120 185 CMFSLISGS 0.120 182SKHCMFSLI 0.120 58 MWTEEAGAT 0.120 92 EDDEAQDSI 0.120 39 IEWQQDRKI 0.110162 SGTWMKLET 0.110 17 AAAWKCLGA 0.100 79 SSSSQIPVV 0.100 140 SQAASGTLS0.100 76 NKSSSSSQI 0.100 142 AASGTLSLA 0.100 105 SPDRALKAA 0.100 57AMWTEEAGA 0.100 144 SGTLSLAFT 0.100 18 AAWKCLGAN 0.100 7 DLSVEVLAS 0.10078 SSSSSQIPV 0.100 12 VLASPAAAW 0.100 73 GIRNKSSSS 0.100 71 ESGIRNKSS0.100 178 QEQKSKHCM 0.075 150 AFTSWSLGE 0.050 46 KIPPLSTPP 0.043 167KLETIILSK 0.042 122 PHTNGVGPL 0.040 21 KCLGANILR 0.030 116 WRNPVLPHT0.025 35 IVLPIEWQQ 0.025 8 LSVEVLASP 0.025 77 KSSSSSQIP 0.024 119PVLPHTNGV 0.022 37 LPIEWQQDR 0.022 1 PSIVILDLS 0.021 6 LDLSVEVLA 0.02132 LSEIVLPIE 0.021 183 KHCMFSLIS 0.020

TABLE XVII V1-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 124 QYPESNAEYL 360.000 359 MYISFGIMSL300.000 399 GYVALLISTF 180.000 282 LYYGTKYRRF 100.000 423 YYRFYTPPNF100.000 290 RFPPWLETWL 86.400 425 RFYTPPNFVL 40.000 186 NFIPIDLGSL36.000 145 GFNVVSAWAL 30.000 40 DFAKSLTIRL 24.000 257 KTLPIVAITL 20.160362 SFGIMSLGLL 20.000 213 RGPVVVAISL 16.800 183 RQLNFIPIDL 16.800 377TSIPSVSNAL 12.096 131 EYLASLFPDS 10.800 250 IPIEIVNKTL 10.080 238PYARNQQSDF 10.000 270 VYLAGLLAAA 9.000 437 VLPSIVILDL 8.400 312FAMVHVAYSL 8.400 279 AYQLYYGTKY 8.250 165 VYICSNNIQA 7.500 176QQVIELARQL 7.200 202 ENLPLRLFTL 7.200 99 TSLWDLRHLL 7.200 427 YTPPNFVLAL7.200 303 KQLGLLSFFF 7.200 267 LSLVYLAGLL 7.200 426 FYTPPNFVLA 7.200 402ALLISTFHVL 7.200 53 GYHVVIGSRN 7.000 247 FYKIPIEIVN 7.000 364 GIMSLGLLSL6.000 127 ESNAEYLASL 6.000 61 RNPKFASEFF 6.000 298 WLQCRKQLGL 6.000 4ISMMGSPKSL 6.000 273 AGLLAAAYQL 6.000 323 LPMRRSERYL 6.000 147NVVSAWALQL 6.000 435 ALVLPSIVIL 6.000 440 SIVILDLLQL 6.000 258TLPIVAITLL 6.000 438 LPSIVILDLL 5.600 422 EYYRFYTPPN 5.000 219AISLATFFFL 4.800 417 RAFEEEYYRF 4.800 365 IMSLGLLSLL 4.800 197SAREIENLPL 4.800 172 IQARQQVIEL 4.400 356 RIEMYISFGI 4.200 36 IGSGDFAKSL4.000 98 YTSLWDLRHL 4.000 132 YLASLFPDSL 4.000 296 ETWLQCRKQL 4.000 266LLSLVYLAGL 4.000 195 LSSAREIENL 4.000 314 MVHVAYSLCL 4.000 263AITLLSLVYL 4.000 299 LQCRKQLGLL 4.000 92 AIHREHYTSL 4.000 361 ISFGIMSLGL4.000 9 SPKSLSETCL 4.000 395 QSTLGYVALL 4.000 394 IQSTLGYVAL 4.000 241RNQQSDFYKI 3.960 163 RQVYICSNNI 3.600 382 VSNALNWREF 3.300 56 VVIGSRNPKF3.300 384 NALNWREFSF 3.000 410 VLIYGWKRAF 3.000 216 VVVAISLATF 3.000 178VIELARQLNF 3.000 218 VAISLATFFF 3.000 200 EIENLPLRLF 3.000 81 DALTKTNIIF3.000 128 SNAEYLASLF 2.880 137 FPDSLIVKGF 2.800 111 KILIDVSNNM 2.520 217VVAISLATFF 2.400 16 TCLPNGINGI 2.160 327 RSERYLFLNM 2.160 13 LSETCLPNGI2.160 396 STLGYVALLI 2.100 432 FVLALVLPSI 2.100 354 VWRIEMYISF 2.000 222LATFFFLYSF 2.000 32 TVGVIGSGDF 2.000 385 ALNWREFSFI 1.800 170 NNIQARQQVI1.800 348 SWNEEEVWRI 1.800 199 REIENLPLRL 1.728 403 LLISTFHVLI 1.500 330RYLFLNMAYQ 1.500 434 LALVLPSIVI 1.500 211 LWRGPVVVAI 1.400 336MAYQQVHANI 1.400 227 FLYSFVRDVI 1.400 103 DLRHLLVGKI 1.320

TABLE XVII V2-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 16 GFTPFSCLSL 24.000 32 RCPPPCPADF7.200 2 GSPGLQALSL 6.000 30 DYRCPPPCPA 5.000 14 SSGFTPFSCL 4.800 11LSLSSGFTPF 3.600 33 CPPPCPADFF 3.600 8 ALSLSLSSGF 2.400 4 PGLQALSLSL0.720 34 PPPCPADFFL 0.600 36 PCPADFFLYF 0.360 9 LSLSLSSGFT 0.150 5GLQALSLSLS 0.150 24 SLPSSWDYRC 0.150 1 SGSPGLQALS 0.144 6 LQALSLSLSS0.120 20 FSCLSLPSSW 0.120 18 TPFSCLSLPS 0.120 15 SGFTPFSCLS 0.100 12SLSSGFTPFS 0.100 28 SWDYRCPPPC 0.100 13 LSSGFTPFSC 0.100 3 SPGLQALSLS0.100 22 CLSLPSSWDY 0.100 19 PFSCLSLPSS 0.050 23 LSLPSSWDYR 0.018 7QALSLSLSSG 0.015 17 FTPFSCLSLP 0.015 21 SCLSLPSSWD 0.015 35 PPCPADFFLY0.014 27 SSWDYRCPPP 0.012 25 LPSSWDYRCP 0.010 10 SLSLSSGFTP 0.010 31YRCPPPCPAD 0.001 29 WDYRCPPPCP 0.001 26 PSSWDYRCPP 0.001

TABLE XVII V5A-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 1 ENLPLRLFTF 3.600 10 FWRGPVVVAI1.400 7 LFTFWRGPVV 0.500 9 TFWRGPVVVA 0.500 2 NLPLRLFTFW 0.216 6RLFTFWRGPV 0.200 8 FTFWRGPVVV 0.100 3 LPLRLFTFWR 0.015 5 LRLFTFWRGP0.002 4 PLRLFTFWRG 0.001

TABLE XVII V5B-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 24 EFVFLLTLLL 36.000 22 ELEFVFLLTL6.000 20 ELELEFVFLL 6.000 12 CSFADTQTEL 4.400 14 FADTQTELEL 4.400 16DTQTELELEF 3.960 18 QTELELEFVF 3.600 5 FSFIQIFCSF 3.360 1 NWREFSFIQI1.440 19 TELELEFVFL 0.864 6 SFIQIFCSFA 0.750 4 EFSFIQIFCS 0.500 10IFCSFADTQT 0.500 23 LEFVFLLTLL 0.480 2 WREFSFIQIF 0.360 8 IQIFCSFADT0.180 17 TQTELELEFV 0.120 13 SFADTQTELE 0.060 21 LELEFVFLLT 0.030 3REFSFIQIFC 0.028 7 FIQIFCSFAD 0.015 11 FCSFADTQTE 0.012 9 QIFCSFADTQ0.010 15 ADTQTELELE 0.001

TABLE XVII V6-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 14 LFLPCISRKL 55.440 7 VILGKIILFL18.400 5 SIVILGKIIL 6.000 6 IVILGKIILF 3.000 35 FLEEGIGGTI 2.520 3LPSIVILGKI 1.540 27 KKGWEKSQFL 0.960 34 QFLEEGIGGT 0.900 46 HVSPERVTVM0.600 11 KIILFLPCIS 0.360 26 IKKGWEKSQF 0.200 4 PSIVILGKII 0.180 38EGIGGTIPHV 0.150 17 PCISRKLKRI 0.150 43 TIPHVSPERV 0.150 10 GKIILFLPCI0.150 9 LGKIILFLPC 0.144 39 GIGGTIPHVS 0.140 31 EKSQFLEEGI 0.120 44IPHVSPERVT 0.100 21 RKLKRIKKGW 0.042 24 KRIKKGWEKS 0.033 32 KSQFLEEGIG0.030 42 GTIPHVSPER 0.028 1 LVLPSIVILG 0.025 28 KGWEKSQFLE 0.024 2VLPSIVILGK 0.021 25 RIKKGWEKSQ 0.020 22 KLKRIKKGWE 0.020 29 GWEKSQFLEE0.020 12 IILFLPCISR 0.015 15 FLPCISRKLK 0.015 8 ILGKIILFLP 0.014 18CISRKLKRIK 0.012 16 LPCISRKLKR 0.011 19 ISRKLKRIKK 0.011 33 SQFLEEGIGG0.010 41 GGTIPHVSPE 0.010 40 IGGTIPHVSP 0.010 13 ILFLPCISRK 0.010 36LEEGIGGTIP 0.002 45 PHVSPERVTV 0.002 20 SRKLKRIKKG 0.001 30 WEKSQFLEEG0.001 23 LKRIKKGWEK 0.001 37 EEGIGGTIPH 0.001

TABLE XVII V7A-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 9 TFLPNGINGI 10.800 2 SPKSLSETFL4.000 1 GSPKSLSETF 3.600 6 LSETFLPNGI 2.160 4 KSLSETFLPN 0.360 10FLPNGINGIK 0.021 5 SLSETFLPNG 0.012 7 SETFLPNGIN 0.010 8 ETFLPNGING0.010 3 PKSLSETFLP 0.000

TABLE XVII V7B-A24- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 6 AYQQSTLGYV 7.500 3 LNMAYQQSTL 6.0008 QQSTLGYVAL 4.000 9 QSTLGYVALL 4.000 10 STLGYVALLI 2.100 1 LFLNMAYQQS0.900 7 YQQSTLGYVA 0.180 2 FLNMAYQQST 0.180 5 MAYQQSTLGY 0.100 4NMAYQQSTLG 0.010

TABLE XVII V7C-HLA-A24- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 168 KLETIILSKL 18.480 151 AFTSWSLGEF11.000 5 VILDLSVEVL 7.200 42 WQQDRKIPPL 7.200 126 NGVGPLWEFL 7.200 102DPPESPDRAL 7.200 113 AANSWRNPVL 6.000 129 GPLWEFLLRL 6.000 148LSLAFTSWSL 6.000 15 ASPAAAWKCL 6.000 165 TWMKLETIIL 6.000 24 LGANILRGGL4.800 20 AWKCLGANIL 4.800 127 GVGPLWEFLL 4.800 152 FTSWSLGEFL 4.800 160FLGSGTWMKL 4.400 122 LPHTNGVGPL 4.000 141 SQAASGTLSL 4.000 182KSKHCMFSLI 2.400 143 AASGTLSLAF 2.400 125 TNGVGPLWEF 2.200 31 GGLSEIVLPI2.100 76 RNKSSSSSQI 2.000 27 NILRGGLSEI 1.650 164 GTWMKLETII 1.200 19AAWKCLGANI 1.200 66 ATAEAQESGI 1.200 163 SGTWMKLETI 1.000 178 TQEQKSKHCM0.750 130 PLWEFLLRLL 0.576 29 LRGGLSEIVL 0.400 181 QKSKHCMFSL 0.400 139LKSQAASGTL 0.400 179 QEQKSKHCMF 0.300 140 KSQAASGTLS 0.300 70 AQESGIRNKS0.277 83 SQIPVVGVVT 0.252 112 KAANSWRNPV 0.240 91 VTEDDEAQDS 0.216 9LSVEVLASPA 0.216 82 SSQIPVVGVV 0.210 78 KSSSSSQIPV 0.200 4 IVILDLSVEV0.198 33 LSEIVLPIEW 0.198 119 NPVLPHTNGV 0.180 105 ESPDRALKAA 0.180 52STPPPPAMWT 0.180 177 LTQEQKSKHC 0.180 134 FLLRLLKSQA 0.180 185HCMFSLISGS 0.180 146 GTLSLAFTSW 0.180 39 PIEWQQDRKI 0.165 88 VGVVTEDDEA0.165 10 SVEVLASPAA 0.150 73 SGIRNKSSSS 0.150 25 GANILRGGLS 0.150 157LGEFLGSGTW 0.150 12 EVLASPAAAW 0.150 156 SLGEFLGSGT 0.144 1 LPSIVILDLS0.140 6 ILDLSVEVLA 0.140 116 SWRNPVLPHT 0.140 43 QQDRKIPPLS 0.140 64AGATAEAQES 0.132 14 LASPAAAWKC 0.132 174 LSKLTQEQKS 0.132 51 LSTPPPPAMW0.120 92 TEDDEAQDSI 0.120 135 LLRLLKSQAA 0.120 106 SPDRALKAAN 0.120 59MWTEEAGATA 0.120 28 ILRGGLSEIV 0.120 154 SWSLGEFLGS 0.120 145 SGTLSLAFTS0.120 162 GSGTWMKLET 0.110 97 AQDSIDPPES 0.110 147 TLSLAFTSWS 0.100 180EQKSKHCMFS 0.100 79 SSSSSQIPVV 0.100 142 QAASGTLSLA 0.100 18 AAAWKCLGAN0.100 138 LLKSQAASGT 0.100 110 ALKAANSWRN 0.100 144 ASGTLSLAFT 0.100 74GIRNKSSSSS 0.100 81 SSSQIPVVGV 0.100 166 WMKLETIILS 0.100 72 ESGIRNKSSS0.100 58 AMWTEEAGAT 0.100 133 EFLLRLLKSQ 0.090 159 EFLGSGTWMK 0.075 158GEFLGSGTWM 0.050 50 PLSTPPPPAM 0.050 47 KIPPLSTPPP 0.036 22 KCLGANILRG0.030 118 RNPVLPHTNG 0.030 109 RALKAANSWR 0.030 137 RLLKSQAASG 0.030 96EAQDSIDPPE 0.025 172 IILSKLTQEQ 0.024

TABLE XVIII V1-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 173 QARQQVIEL 120.000 214 GPVVVAISL80.000 259 LPIVAITLL 80.000 428 TPPNFVLAL 80.000 438 LPSIVILDL 80.000291 FPPWLETWL 80.000 300 QCRKQLGLL 40.000 125 YPESNAEYL 24.000 177QVIELARQL 20.000 148 VVSAWALQL 20.000 261 IVAITLLSL 20.000 75 DVTHHEDAL20.000 441 IVILDLLQL 20.000 436 LPLPSIVIL 20.000 41 FAKSLTIRL 12.000 313AMVHVAYSL 12.000 133 LASLFPDSL 12.000 5 SMMGSPKSL 12.000 27 DARKVTVGV6.000 100 SLWDLRHLL 6.000 146 FNVVSAWAL 4.000 220 ISLATFFFL 4.000 187FIPIDLGSL 4.000 128 SNAEYLASL 4.000 363 FGIMSLGLL 4.000 274 GLLAAAYQL4.000 365 IMSLGLLSL 4.000 366 MSLGLLSLL 4.000 184 QLNFIPIDL 4.000 93IHREHYTSL 4.000 324 PMRRSERYL 4.000 395 QSTLGYVAL 4.000 267 LSLVYLAGL4.000 268 SLVYLAGLL 4.000 360 YISFGIMSL 4.000 196 SSAREIENL 4.000 378SIPSVSNAL 4.000 258 TLPIVAITL 4.000 299 LQCRKQLGL 4.000 99 TSLWDLRHL4.000 403 LLISTFHVL 4.000 37 GSGDFAKSL 4.000 203 NLPLRLFTL 4.000 264ITLLSLVYL 4.000 396 STLGYVALL 4.000 287 KYRRFPPWL 4.000 157 GPKDASRQV4.000 317 VAYSLCLPM 3.000 9 SPKSLSETC 2.000 250 IPIEIVNKT 2.000 353EVWRIEMYI 2.000 49 LIRCGYHVV 2.000 164 QVYICSNNI 2.000 134 ASLFPDSLI1.800 435 ALVLPSIVI 1.800 200 EIENLPLRL 1.200 81 DALTKTNII 1.200 323LPMRRSERY 1.200 108 LVGKILIDV 1.000 358 EMYISFGIM 1.000 112 ILIDVSNNM1.000 254 IVNKTLPIV 1.000 231 FVRDVIHPY 1.000 328 SERYLFLNM 1.000 306GLLSFFFAM 1.000 278 AAYQLYYGT 0.900 402 ALLISTFHV 0.600 297 TWLQCRKQL0.600 262 VAITLLSLV 0.600 239 YARNQQSDF 0.600 434 LALVLPSIV 0.600 65FASEFFPHV 0.600 161 ASRQVYICS 0.600 426 FYTPPNFVL 0.600 374 LAVTSIPSV0.600 314 MVHVAYSLC 0.500 34 GVIGSGDFA 0.500 216 VVVAISLAT 0.500 269LVYLAGLLA 0.500 237 HPYARNQQS 0.400 371 LSLLAVTSI 0.400 85 KTNIIFVAI0.400 390 EFSFIQSTL 0.400 439 PSIVILDLL 0.400 397 TLGYVALLI 0.400 430PNFVLALVL 0.400 362 SFGIMSLGL 0.400 171 NIQARQQVI 0.400 180 ELARQLNFI0.400 193 GSLSSAREI 0.400 386 LNWREFSFI 0.400 204 LPLRLFTLW 0.400 429PPNFVLALV 0.400 188 IPIDLGSLS 0.400 379 IPSVSNALN 0.400 62 NPKFASEFF0.400 326 RRSERYLFL 0.400 433 VLALVLPSI 0.400 253 EIVNKTLPI 0.400 106HLLVGKILI 0.400

TABLE XVIII V2-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 3 SPGLQALSL 80.000 35 PPCPADFFL8.000 15 SGFTPFSCL 6.000 1 SGSPGLQAL 4.000 17 FTPFSCLSL 4.000 5GLQALSLSL 4.000 25 LPSSWDYRC 2.000 37 CPADFFLYF 0.400 33 CPPPCPADF 0.40018 TPFSCLSLP 0.200 10 SLSLSSGFT 0.100 14 SSGFTPFSC 0.100 7 QALSLSLSS0.060 34 PPPCPADFF 0.060 8 ALSLSLSSG 0.030 23 LSLPSSWDY 0.020 12SLSSGFTPF 0.020 21 SCLSLPSSW 0.020 6 LQALSLSLS 0.020 13 LSSGFTPFS 0.0202 GSPGLQALS 0.020 9 LSLSLSSGF 0.020 20 FSCLSLPSS 0.020 32 RCPPPCPAD0.015 22 CLSLPSSWD 0.015 31 YRCPPPCPA 0.015 30 DYRCPPPCP 0.015 27SSWDYRCPP 0.015 29 WDYRCPPPC 0.010 24 SLPSSWDYR 0.010 11 LSLSSGFTP 0.01036 PCPADFFLY 0.002 16 GFTPFSCLS 0.002 4 PGLQALSLS 0.002 26 PSSWDYRCP0.001 28 SWDYRCPPP 0.000 19 PFSCLSLPS 0.000

TABLE XVIII V5A-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 LPLRLFTFW 0.400 7 FTFWRGPVV 0.2009 FWRGPVVVA 0.150 6 LFTFWRGPV 0.030 8 TFWRGPVVV 0.020 1 NLPLRLFTF 0.0203 PLRLFTFWR 0.010 5 RLFTFWRGP 0.010 4 LRLFTFWRG 0.001

TABLE XVIII V5B-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 24 FVFLLTLLL 20.000 14 ADTQTELEL1.200 19 ELELEFVFL 1.200 12 SFADTQTEL 0.400 23 EFVFLLTLL 0.400 22LEFVFLLTL 0.400 20 LELEFVFLL 0.400 10 FCSFADTQT 0.100 8 QIFCSFADT 0.1006 FIQIFCSFA 0.100 17 QTELELEFV 0.060 21 ELEFVFLLT 0.030 4 FSFIQIFCS0.020 16 TQTELELEF 0.020 1 WREFSFIQI 0.012 11 CSFADTQTE 0.010 3EFSFIQIFC 0.010 7 IQIFCSFAD 0.010 15 DTQTELELE 0.010 13 FADTQTELE 0.0095 SFIQIFCSF 0.002 2 REFSFIQIF 0.002 18 TELELEFVF 0.002 9 IFCSFADTQ 0.001

TABLE XVIII V6-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 5 IVILGKIIL 20.000 14 FLPCISRKL4.000 43 IPHVSPERV 4.000 7 ILGKIILFL 4.000 27 KGWEKSQFL 4.000 45HVSPERVTV 1.500 46 VSPERVTVM 1.000 31 KSQFLEEGI 0.400 4 SIVILGKII 0.40017 CISRKLKRI 0.400 10 KIILFLPCI 0.400 15 LPCISRKLK 0.300 38 GIGGTIPHV0.200 2 LPSIVILGK 0.200 18 ISRKLKRIK 0.100 3 PSIVILGKI 0.040 34FLEEGIGGT 0.030 11 IILFLPCIS 0.020 39 IGGTIPHVS 0.020 6 VILGKIILF 0.02024 RIKKGWEKS 0.020 21 KLKRIKKGW 0.020 40 GGTIPHVSP 0.015 12 ILFLPCISR0.015 35 LEEGIGGTI 0.012 37 EGIGGTIPH 0.010 22 LKRIKKGWE 0.010 8LGKIILFLP 0.010 32 SQFLEEGIG 0.010 41 GTIPHVSPE 0.010 1 VLPSIVILG 0.0109 GKIILFLPC 0.010 42 TIPHVSPER 0.010 26 KKGWEKSQF 0.002 19 SRKLKRIKK0.002 44 PHVSPERVT 0.002 36 EEGIGGTIP 0.001 20 RKLKRIKKG 0.001 29WEKSQFLEE 0.001 13 LFLPCISRK 0.001 25 IKKGWEKSQ 0.001 30 EKSQFLEEG 0.00133 QFLEEGIGG 0.001 23 KRIKKGWEK 0.001 16 PCISRKLKR 0.001 28 GWEKSQFLE0.000

TABLE XVIII V7A-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 FLPNGINGI 0.400 1 SPKSLSETF 0.4006 SETFLPNGI 0.040 2 PKSLSETFL 0.040 7 ETFLPNGIN 0.030 4 SLSETFLPN 0.0203 KSLSETFLP 0.010 5 LSETFLPNG 0.003 8 TFLPNGING 0.001

TABLE XVIII V7B-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 STLGYVALL 4.000 8 QSTLGYVAL 4.0003 NMAYQQSTL 4.000 2 LNMAYQQST 0.300 6 YQQSTLGYV 0.200 7 QQSTLGYVA 0.1004 MAYQQSTLG 0.030 1 FLNMAYQQS 0.020 5 AYQQSTLGY 0.006

TABLE XVIII V7C-HLA-B7- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 15 SPAAAWKCL 80.000 126 GVGPLWEFL20.000 24 GANILRGGL 18.000 113 ANSWRNPVL 12.000 141 QAASGTLSL 12.000 127VGPLWEFLL 4.000 148 SLAFTSWSL 4.000 181 KSKHCMFSL 4.000 29 RGGLSEIVL4.000 139 KSQAASGTL 4.000 27 ILRGGLSEI 4.000 165 WMKLETIIL 4.000 152TSWSLGEFL 4.000 160 LGSGTWMKL 4.000 102 PPESPDRAL 3.600 52 TPPPPAMWT3.000 112 AANSWRNPV 2.700 101 DPPESPDRA 2.000 50 LSTPPPPAM 1.500 5ILDLSVEVL 1.200 42 QQDRKIPPL 1.200 134 LLRLLKSQA 1.000 142 AASGTLSLA0.900 17 AAAWKCLGA 0.900 105 SPDRALKAA 0.600 11 EVLASPAAA 0.500 88GVVTEDDEA 0.500 31 GLSEIVLPI 0.400 20 WKCLGANIL 0.400 168 LETIILSKL0.400 163 GTWMKLETI 0.400 129 PLWEFLLRL 0.400 66 TAEAQESGI 0.360 81SSQIPVVGV 0.300 57 AMWTEEAGA 0.300 14 ASPAAAWKC 0.300 118 NPVLPHTNG0.300 84 IPVVGVVTE 0.200 79 SSSSQIPVV 0.200 55 PPAMWTEEA 0.200 82SQIPVVGVV 0.200 37 LPIEWQQDR 0.200 78 SSSSSQIPV 0.200 73 GIRNKSSSS 0.2004 VILDLSVEV 0.200 2 SIVILDLSV 0.200 47 IPPLSTPPP 0.200 128 GPLWEFLLR0.200 121 LPHTNGVGP 0.200 18 AAWKCLGAN 0.180 9 SVEVLASPA 0.150 164TWMKLETII 0.120 19 AWKCLGANI 0.120 130 LWEFLLRLL 0.120 104 ESPDRALKA0.100 158 EFLGSGTWM 0.100 162 SGTWMKLET 0.100 169 ETIILSKLT 0.100 83QIPVVGVVT 0.100 178 QEQKSKHCM 0.100 144 SGTLSLAFT 0.100 119 PVLPHTNGV0.100 143 ASGTLSLAF 0.060 64 GATAEAQES 0.060 68 EAQESGIRN 0.060 25ANILRGGLS 0.060 108 RALKAANSW 0.060 35 IVLPIEWQQ 0.050 86 VVGVVTEDD0.050 3 IVILDLSVE 0.050 89 VVTEDDEAQ 0.050 122 PHTNGVGPL 0.040 76NKSSSSSQI 0.040 182 SKHCMFSLI 0.040 39 IEWQQDRKI 0.040 12 VLASPAAAW0.030 62 EAGATAEAQ 0.030 125 NGVGPLWEF 0.030 13 LASPAAAWK 0.030 109ALKAANSWR 0.030 63 AGATAEAQE 0.030 95 EAQDSIDPP 0.030 65 ATAEAQESG 0.030149 LAFTSWSLG 0.030 111 KAANSWRNP 0.030 51 STPPPPAMW 0.030 184 HCMFSLISG0.030 59 WTEEAGATA 0.030 156 LGEFLGSGT 0.030 177 TQEQKSKHC 0.030 140SQAASGTLS 0.020 48 PPLSTPPPP 0.020 71 ESGIRNKSS 0.020 123 HTNGVGPLW0.020 72 SGIRNKSSS 0.020 179 EQKSKHCMF 0.020 185 CMFSLISGS 0.020 54PPPAMWTEE 0.020 147 LSLAFTSWS 0.020 28 LRGGLSEIV 0.020

TABLE XIX V1-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 323 LPMRRSERYL 240.000 197 SAREIENLPL120.000 438 LPSIVILDLL 80.000 9 SPKSLSETCL 80.000 250 IPIEIVNKTL 80.000312 FAMVHVAYSL 36.000 147 NVVSAWALQL 20.000 314 MVHVAYSLCL 20.000 364GIMSLGLLSL 12.000 263 AITLLSLVYL 12.000 219 AISLATFFFL 12.000 402ALLISTFHVL 12.000 435 ALVLPSIVIL 12.000 273 AGLLAAAYQL 12.000 4ISMMGSPKSL 12.000 92 AIHREHYTSL 12.000 27 DARKVTVGVI 12.000 181LARQLNFIPI 12.000 429 PPNFVLALVL 8.000 296 ETWLQCRKQL 6.000 99TSLWDLRHLL 6.000 316 HVAYSLCLPM 5.000 231 FVRDVIHPYA 5.000 195LSSAREIENL 4.000 257 KTLPIVAITL 4.000 377 TSIPSVSNAL 4.000 266LLSLVYLAGL 4.000 202 ENLPLRLFTL 4.000 132 YLASLFPDSL 4.000 299LQCRKQLGLL 4.000 176 QQVIELARQL 4.000 427 YTPPNFVLAL 4.000 394IQSTLGYVAL 4.000 213 RGPVVVAISL 4.000 365 IMSLGLLSLL 4.000 49 LIRCGYHVVI4.000 428 TPPNFVLALV 4.000 103 DLRHLLVGKI 4.000 36 IGSGDFAKSL 4.000 98YTSLWDLRHL 4.000 298 WLQCRKQLGL 4.000 325 MRRSERYLFL 4.000 361ISFGIMSLGL 4.000 258 TLPIVAITLL 4.000 172 IQARQQVIEL 4.000 127ESNAEYLASL 4.000 440 SIVILDLLQL 4.000 183 RQLNFIPIDL 4.000 267LSLVYLAGLL 4.000 437 VLPSIVILDL 4.000 395 QSTLGYVALL 4.000 173QARQQVIELA 3.000 432 FVLALVLPSI 2.000 214 GPVVVAISLA 2.000 434LALVLPSIVI 1.800 133 LASLFPDSLI 1.800 385 ALNWREFSFI 1.200 336MAYQQVHANI 1.200 41 FAKSLTIRLI 1.200 111 KILIDVSNNM 1.000 261 IVAITLLSLV1.000 305 LGLLSFFFAM 1.000 277 AAAYQLYYGT 0.900 161 ASRQVYICSN 0.600 239YARNQQSDFY 0.600 255 VNKTLPIVAI 0.600 401 VALLISTFHV 0.600 125YPESNAEYLA 0.600 157 GPKDASRQVY 0.600 227 FLYSFVRDVI 0.600 82 ALTKTNIIFV0.600 425 RFYTPPNFVL 0.600 65 FASEFFPHVV 0.600 134 ASLFPDSLIV 0.600 223ATFFFLYSFV 0.600 269 LVYLAGLLAA 0.500 142 IVKGFNVVSA 0.500 75 DVTHHEDALT0.500 441 IVILDLLQLC 0.500 409 HVLIYGWKRA 0.500 254 IVNKTLPIVA 0.500 90FVAIHREHYT 0.500 375 AVTSIPSVSN 0.450 199 REIENLPLRL 0.400 95 REHYTSLWDL0.400 379 IPSVSNALNW 0.400 259 LPIVAITLLS 0.400 211 LWRGPVVVAI 0.400 163RQVYICSNNI 0.400 145 GFNVVSAWAL 0.400 186 NFIPIDLGSL 0.400 188IPIDLGSLSS 0.400 370 LLSLLAVTSI 0.400 359 MYISFGIMSL 0.400 16 TCLPNGINGI0.400 124 QYPESNAEYL 0.400 170 NNIQARQQVI 0.400 243 QQSDFYKIPI 0.400 241RNQQSDFYKI 0.400 74 VDVTHHEDAL 0.400

TABLE XIX V2-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 34 PPPCPADFFL 8.000 14 SSGFTPFSCL6.000 2 GSPGLQALSL 4.000 33 CPPPCPADFF 0.600 18 TPFSCLSLPS 0.400 16GFTPFSCLSL 0.400 3 SPGLQALSLS 0.400 4 PGLQALSLSL 0.400 25 LPSSWDYRCP0.200 30 DYRCPPPCPA 0.150 24 SLPSSWDYRC 0.100 13 LSSGFTPFSC 0.100 9LSLSLSSGFT 0.100 8 ALSLSLSSGF 0.060 35 PPCPADFFLY 0.040 7 QALSLSLSSG0.030 15 SGFTPFSCLS 0.020 22 CLSLPSSWDY 0.020 11 LSLSSGFTPF 0.020 6LQALSLSLSS 0.020 32 RCPPPCPADF 0.020 1 SGSPGLQALS 0.020 20 FSCLSLPSSW0.020 12 SLSSGFTPFS 0.020 5 GLQALSLSLS 0.020 21 SCLSLPSSWD 0.015 10SLSLSSGFTP 0.010 17 FTPFSCLSLP 0.010 27 SSWDYRCPPP 0.010 23 LSLPSSWDYR0.010 28 SWDYRCPPPC 0.003 36 PCPADFFLYF 0.002 26 PSSWDYRCPP 0.002 31YRCPPPCPAD 0.002 29 WDYRCPPPCP 0.002 19 PFSCLSLPSS 0.000

TABLE XIX V5A-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 10 FWRGPVVVAI 0.400 6 RLFTFWRGPV0.300 8 FTFWRGPVVV 0.200 3 LPLRLFTFWR 0.200 2 NLPLRLFTFW 0.020 7LFTFWRGPVV 0.020 1 ENLPLRLFTF 0.020 9 TFWRGPVVVA 0.015 4 PLRLFTFWRG0.010 5 LRLFTFWRGP 0.001

TABLE XIX V5B-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 12 CSFADTQTEL 4.000 14 FADTQTELEL3.600 20 ELELEFVFLL 1.200 22 ELEFVFLLTL 1.200 23 LEFVFLLTLL 0.400 1NWREFSFIQI 0.400 19 TELELEFVFL 0.400 24 EFVFLLTLLL 0.400 17 TQTELELEFV0.200 8 IQIFCSFADT 0.100 5 FSFIQIFCSF 0.020 16 DTQTELELEF 0.020 10IFCSFADTQT 0.010 21 LELEFVFLLT 0.010 6 SFIQIFCSFA 0.010 3 REFSFIQIFC0.010 9 QIFCSFADTQ 0.010 7 FIQIFCSFAD 0.010 11 FCSFADTQTE 0.010 18QTELELEFVF 0.006 15 ADTQTELELE 0.003 4 EFSFIQIFCS 0.002 13 SFADTQTELE0.001 2 WREFSFIQIF 0.001

TABLE XIX V6-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 LPSIVILGKI 8.000 46 HVSPERVTVM5.000 5 SIVILGKIIL 4.000 7 VILGKIILFL 4.000 44 IPHVSPERVT 3.000 14LFLPCISRKL 0.400 27 KKGWEKSQFL 0.400 16 LPCISRKLKR 0.200 43 TIPHVSPERV0.200 38 EGIGGTIPHV 0.200 19 ISRKLKRIKK 0.150 35 FLEEGIGGTI 0.120 9LGKIILFLPC 0.100 6 IVILGKIILF 0.100 1 LVLPSIVILG 0.050 10 GKIILFLPCI0.040 4 PSIVILGKII 0.040 31 EKSQFLEEGI 0.040 17 PCISRKLKRI 0.040 11KIILFLPCIS 0.020 39 GIGGTIPHVS 0.020 15 FLPCISRKLK 0.015 40 IGGTIPHVSP0.015 12 IILFLPCISR 0.015 34 QFLEEGIGGT 0.010 2 VLPSIVILGK 0.010 33SQFLEEGIGG 0.010 25 RIKKGWEKSQ 0.010 32 KSQFLEEGIG 0.010 13 ILFLPCISRK0.010 22 KLKRIKKGWE 0.010 8 ILGKIILFLP 0.010 41 GGTIPHVSPE 0.010 18CISRKLKRIK 0.010 28 KGWEKSQFLE 0.010 42 GTIPHVSPER 0.010 23 LKRIKKGWEK0.010 45 PHVSPERVTV 0.003 24 KRIKKGWEKS 0.002 26 IKKGWEKSQF 0.002 21RKLKRIKKGW 0.002 20 SRKLKRIKKG 0.001 37 EEGIGGTIPH 0.001 30 WEKSQFLEEG0.001 29 GWEKSQFLEE 0.000 36 LEEGIGGTIP 0.000

TABLE XIX V7A-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 SPKSLSETFL 80.000 6 LSETFLPNGI0.120 9 TFLPNGINGI 0.040 1 GSPKSLSETF 0.020 4 KSLSETFLPN 0.020 10FLPNGINGIK 0.010 5 SLSETFLPNG 0.010 8 ETFLPNGING 0.010 7 SETFLPNGIN0.003 3 PKSLSETFLP 0.000

TABLE XIX V7B-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 LNMAYQQSTL 12.000 8 QQSTLGYVAL4.000 9 QSTLGYVALL 4.000 10 STLGYVALLI 0.400 7 YQQSTLGYVA 0.100 2FLNMAYQQST 0.100 6 AYQQSTLGYV 0.060 5 MAYQQSTLGY 0.060 4 NMAYQQSTLG0.010 1 LFLNMAYQQS 0.002

TABLE XIX V7C-HLA-B7- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 102 DPPESPDRAL 120.000 122 LPHTNGVGPL80.000 129 GPLWEFLLRL 80.000 113 AANSWRNPVL 36.000 127 GVGPLWEFLL 20.00015 ASPAAAWKCL 12.000 24 LGANILRGGL 6.000 152 FTSWSLGEFL 4.000 42WQQDRKIPPL 4.000 160 FLGSGTWMKL 4.000 5 VILDLSVEVL 4.000 126 NGVGPLWEFL4.000 141 SQAASGTLSL 4.000 119 NPVLPHTNGV 4.000 148 LSLAFTSWSL 4.000 19AAWKCLGANI 3.600 28 ILRGGLSEIV 2.000 168 KLETIILSKL 1.200 20 AWKCLGANIL1.200 165 TWMKLETIIL 1.200 66 ATAEAQESGI 1.200 4 IVILDLSVEV 1.000 135LLRLLKSQAA 1.000 112 KAANSWRNPV 0.900 164 GTWMKLETII 0.400 139LKSQAASGTL 0.400 181 QKSKHCMFSL 0.400 76 RNKSSSSSQI 0.400 29 LRGGLSEIVL0.400 1 LPSIVILDLS 0.400 130 PLWEFLLRLL 0.400 27 NILRGGLSEI 0.400 31GGLSEIVLPI 0.400 163 SGTWMKLETI 0.400 182 KSKHCMFSLI 0.400 144ASGTLSLAFT 0.300 49 PPLSTPPPPA 0.300 81 SSSQIPVVGV 0.300 142 QAASGTLSLA0.300 14 LASPAAAWKC 0.300 58 AMWTEEAGAT 0.300 178 TQEQKSKHCM 0.300 16SPAAAWKCLG 0.200 85 IPVVGVVTED 0.200 82 SSQIPVVGVV 0.200 48 IPPLSTPPPP0.200 55 PPPAMWTEEA 0.200 78 KSSSSSQIPV 0.200 79 SSSSSQIPVV 0.200 74GIRNKSSSSS 0.200 53 TPPPPAMWTE 0.200 38 LPIEWQQDRK 0.200 18 AAAWKCLGAN0.180 143 AASGTLSLAF 0.180 50 PLSTPPPPAM 0.150 10 SVEVLASPAA 0.150 52STPPPPAMWT 0.150 44 QDRKIPPLST 0.150 12 EVLASPAAAW 0.150 106 SPDRALKAAN0.120 158 GEFLGSGTWM 0.100 156 SLGEFLGSGT 0.100 162 GSGTWMKLET 0.100 88VGVVTEDDEA 0.100 134 FLLRLLKSQA 0.100 138 LLKSQAASGT 0.100 177LTQEQKSKHC 0.100 83 SQIPVVGVVT 0.100 105 ESPDRALKAA 0.100 116 SWRNPVLPHT0.100 9 LSVEVLASPA 0.100 57 PAMWTEEAGA 0.090 185 HCMFSLISGS 0.060 110ALKAANSWRN 0.060 25 GANILRGGLS 0.060 64 AGATAEAQES 0.060 36 IVLPIEWQQD0.050 87 VVGVVTEDDE 0.050 90 VVTEDDEAQD 0.050 89 GVVTEDDEAQ 0.050 150LAFTSWSLGE 0.030 125 TNGVGPLWEF 0.030 109 RALKAANSWR 0.030 96 EAQDSIDPPE0.030 63 EAGATAEAQE 0.030 26 ANILRGGLSE 0.030 51 LSTPPPPAMW 0.030 69EAQESGIRNK 0.030 17 PAAAWKCLGA 0.030 65 GATAEAQESG 0.030 114 ANSWRNPVLP0.030 6 ILDLSVEVLA 0.030 70 AQESGIRNKS 0.027 147 TLSLAFTSWS 0.020 146GTLSLAFTSW 0.020 140 KSQAASGTLS 0.020 180 EQKSKHCMFS 0.020 56 PPAMWTEEAG0.020 145 SGTLSLAFTS 0.020 72 ESGIRNKSSS 0.020

TABLE XX V1-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 62 NPKFASEFF 60.000 323 LPMRRSERY40.000 157 GPKDASRQV 24.000 259 LPIVAITLL 20.000 428 TPPNFVLAL 20.000291 FPPWLETWL 20.000 438 LPSIVILDL 20.000 214 GPVVVAISL 20.000 231FVRDVIHPY 12.000 37 GSGDFAKSL 10.000 405 ISTFHVLIY 10.000 204 LPLRLFTLW10.000 239 YARNQQSDF 9.000 41 FAKSLTIRL 9.000 173 QARQQVIEL 9.000 99TSLWDLRHL 7.500 196 SSAREIENL 7.500 9 SPKSLSETC 6.000 317 VAYSLCLPM6.000 276 LAAAYQLYY 6.000 272 LAGLLAAAY 6.000 125 YPESNAEYL 6.000 46TIRLIRCGY 6.000 267 LSLVYLAGL 5.000 395 QSTLGYVAL 5.000 366 MSLGLLSLL5.000 220 ISLATFFFL 5.000 250 IPIEIVNKT 4.000 112 ILIDVSNNM 4.000 188IPIDLGSLS 4.000 347 NSWNEEEVW 3.750 133 LASLFPDSL 3.000 300 QCRKQLGLL3.000 218 VAISLATFF 3.000 177 QVIELARQL 2.000 303 KQLGLLSFF 2.000 371LSLLAVTSI 2.000 128 SNAEYLASL 2.000 275 LLAAAYQLY 2.000 61 RNPKFASEF2.000 100 SLWDLRHLL 2.000 237 HPYARNQQS 2.000 379 IPSVSNALN 2.000 117SNNMRINQY 2.000 306 GLLSFFFAM 2.000 134 ASLFPDSLI 2.000 221 SLATFFFLY2.000 193 GSLSSAREI 2.000 263 AITLLSLVY 2.000 90 FVAIHREHY 2.000 280YQLYYGTKY 2.000 358 EMYISFGIM 2.000 27 DARKVTVGV 1.800 441 IVILDLLQL1.500 161 ASRQVYICS 1.500 59 GSRNPKFAS 1.500 187 FIPIDLGSL 1.500 81DALTKTNII 1.200 65 FASEFFPHV 1.200 365 IMSLGLLSL 1.000 184 QLNFIPIDL1.000 385 ALNWREFSF 1.000 148 VVSAWALQL 1.000 274 GLLAAAYQL 1.000 144KGFNVVSAW 1.000 146 FNVVSAWAL 1.000 383 SNALNWREF 1.000 304 QLGLLSFFF1.000 363 FGIMSLGLL 1.000 217 VVAISLATF 1.000 57 VIGSRNPKF 1.000 313AMVHVAYSL 1.000 411 LIYGWKRAF 1.000 378 SIPSVSNAL 1.000 264 ITLLSLVYL1.000 75 DVTHHEDAL 1.000 436 LVLPSIVIL 1.000 82 ALTKTNIIF 1.000 403LLISTFHVL 1.000 299 LQCRKQLGL 1.000 400 YVALLISTF 1.000 258 TLPIVAITL1.000 268 SLVYLAGLL 1.000 5 SMMGSPKSL 1.000 223 ATFFFLYSF 1.000 33VGVIGSGDF 1.000 396 STLGYVALL 1.000 261 IVAITLLSL 1.000 360 YISFGIMSL1.000 219 AISLATFFF 1.000 203 NLPLRLFTL 1.000 129 NAEYLASLF 0.900 85KTNIIFVAI 0.800 127 ESNAEYLAS 0.750 386 LNWREFSFI 0.600 434 LALVLPSIV0.600 416 KRAFEEEYY 0.600 328 SERYLFLNM 0.600 287 KYRRFPPWL 0.600 24GIKDARKVT 0.600

TABLE XX V2-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 37 CPADFFLYF 40.000 33 CPPPCPADF20.000 3 SPGLQALSL 20.000 23 LSLPSSWDY 10.000 9 LSLSLSSGF 5.000 35PPCPADFFL 2.000 34 PPPCPADFF 2.000 25 LPSSWDYRC 2.000 15 SGFTPFSCL 1.0001 SGSPGLQAL 1.000 12 SLSSGFTPF 1.000 5 GLQALSLSL 1.000 17 FTPFSCLSL1.000 20 FSCLSLPSS 0.500 2 GSPGLQALS 0.500 13 LSSGFTPFS 0.500 14SSGFTPFSC 0.500 21 SCLSLPSSW 0.500 7 QALSLSLSS 0.300 36 PCPADFFLY 0.30018 TPFSCLSLP 0.200 6 LQALSLSLS 0.100 10 SLSLSSGFT 0.100 27 SSWDYRCPP0.100 11 LSLSSGFTP 0.050 32 RCPPPCPAD 0.020 8 ALSLSLSSG 0.010 22CLSLPSSWD 0.010 29 WDYRCPPPC 0.010 24 SLPSSWDYR 0.010 31 YRCPPPCPA 0.0104 PGLQALSLS 0.010 16 GFTPFSCLS 0.010 26 PSSWDYRCP 0.008 30 DYRCPPPCP0.003 19 PFSCLSLPS 0.001 28 SWDYRCPPP 0.000

TABLE XX V5A-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 LPLRLFTFW 10.000 1 NLPLRLFTF 1.0007 FTFWRGPVV 0.200 9 FWRGPVVVA 0.030 6 LFTFWRGPV 0.020 5 RLFTFWRGP 0.0208 TFWRGPVVV 0.020 3 PLRLFTFWR 0.003 4 LRLFTFWRG 0.001

TABLE XX V5B-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 16 TQTELELEF 2.000 24 FVFLLTLLL1.000 4 FSFIQIFCS 0.500 19 ELELEFVFL 0.450 12 SFADTQTEL 0.200 18TELELEFVF 0.200 20 LELEFVFLL 0.200 2 REFSFIQIF 0.200 22 LEFVFLLTL 0.10010 FCSFADTQT 0.100 8 QIFCSFADT 0.100 23 EFVFLLTLL 0.100 6 FIQIFCSFA0.100 14 ADTQTELEL 0.100 5 SFIQIFCSF 0.100 17 QTELELEFV 0.090 11CSFADTQTE 0.075 21 ELEFVFLLT 0.030 15 DTQTELELE 0.015 1 WREFSFIQI 0.0127 IQIFCSFAD 0.010 3 EFSFIQIFC 0.010 13 FADTQTELE 0.009 9 IFCSFADTQ 0.001

TABLE XX V6-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 46 VSPERVTVM 20.000 27 KGWEKSQFL4.000 43 IPHVSPERV 4.000 31 KSQFLEEGI 4.000 21 KLKRIKKGW 3.000 14FLPCISRKL 1.000 6 VILGKIILF 1.000 5 IVILGKIIL 1.000 7 ILGKIILFL 1.000 10KIILFLPCI 0.800 24 RIKKGWEKS 0.600 17 CISRKLKRI 0.400 4 SIVILGKII 0.40045 HVSPERVTV 0.300 26 KKGWEKSQF 0.300 2 LPSIVILGK 0.200 15 LPCISRKLK0.200 38 GIGGTIPHV 0.200 3 PSIVILGKI 0.200 18 ISRKLKRIK 0.150 39IGGTIPHVS 0.100 11 IILFLPCIS 0.100 34 FLEEGIGGT 0.060 8 LGKIILFLP 0.03032 SQFLEEGIG 0.015 35 LEEGIGGTI 0.012 37 EGIGGTIPH 0.010 41 GTIPHVSPE0.010 40 GGTIPHVSP 0.010 1 VLPSIVILG 0.010 9 GKIILFLPC 0.010 12ILFLPCISR 0.010 42 TIPHVSPER 0.010 33 QFLEEGIGG 0.003 29 WEKSQFLEE 0.00325 IKKGWEKSQ 0.003 22 LKRIKKGWE 0.003 19 SRKLKRIKK 0.003 20 RKLKRIKKG0.002 23 KRIKKGWEK 0.002 44 PHVSPERVT 0.001 13 LFLPCISRK 0.001 30EKSQFLEEG 0.001 16 PCISRKLKR 0.001 36 EEGIGGTIP 0.001 28 GWEKSQFLE 0.000

TABLE XX V7A-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 SPKSLSETF 60.000 9 FLPNGINGI 0.4004 SLSETFLPN 0.200 3 KSLSETFLP 0.150 7 ETFLPNGIN 0.100 6 SETFLPNGI 0.0405 LSETFLPNG 0.015 2 PKSLSETFL 0.010 8 TFLPNGING 0.001

TABLE XX V7B-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 8 QSTLGYVAL 5.000 9 STLGYVALL 1.0003 NMAYQQSTL 1.000 6 YQQSTLGYV 0.200 5 AYQQSTLGY 0.200 7 QQSTLGYVA 0.1001 FLNMAYQQS 0.100 2 LNMAYQQST 0.100 4 MAYQQSTLG 0.030

TABLE XX V7C-HLA-B3501- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 181 KSKHCMFSL 30.000 15 SPAAAWKCL20.000 139 KSQAASGTL 10.000 50 LSTPPPPAM 10.000 152 TSWSLGEFL 5.000 143ASGTLSLAF 5.000 165 WMKLETIIL 4.500 101 DPPESPDRA 4.000 179 EQKSKHCMF3.000 24 GANILRGGL 3.000 141 QAASGTLSL 3.000 108 RALKAANSW 3.000 29RGGLSEIVL 2.000 52 TPPPPAMWT 2.000 27 ILRGGLSEI 1.200 78 SSSSSQIPV 1.000126 GVGPLWEFL 1.000 113 ANSWRNPVL 1.000 104 ESPDRALKA 1.000 160LGSGTWMKL 1.000 127 VGPLWEFLL 1.000 79 SSSSQIPVV 1.000 148 SLAFTSWSL1.000 151 FTSWSLGEF 1.000 125 NGVGPLWEF 1.000 81 SSQIPVVGV 1.000 31GLSEIVLPI 0.800 154 WSLGEFLGS 0.750 102 PPESPDRAL 0.600 112 AANSWRNPV0.600 105 SPDRALKAA 0.600 68 EAQESGIRN 0.600 51 STPPPPAMW 0.500 147LSLAFTSWS 0.500 146 TLSLAFTSW 0.500 12 VLASPAAAW 0.500 71 ESGIRNKSS0.500 123 HTNGVGPLW 0.500 14 ASPAAAWKC 0.500 64 GATAEAQES 0.450 163GTWMKLETI 0.400 37 LPIEWQQDR 0.400 4 VILDLSVEV 0.400 66 TAEAQESGI 0.360134 LLRLLKSQA 0.300 42 QQDRKIPPL 0.300 73 GIRNKSSSS 0.300 17 AAAWKCLGA0.300 142 AASGTLSLA 0.300 128 GPLWEFLLR 0.300 18 AAWKCLGAN 0.300 5ILDLSVEVL 0.300 136 RLLKSQAAS 0.200 82 SQIPVVGVV 0.200 47 IPPLSTPPP0.200 55 PPAMWTEEA 0.200 121 LPHTNGVGP 0.200 129 PLWEFLLRL 0.200 178QEQKSKHCM 0.200 117 RNPVLPHTN 0.200 2 SIVILDLSV 0.200 158 EFLGSGTWM0.200 84 IPVVGVVTE 0.200 118 NPVLPHTNG 0.200 57 AMWTEEAGA 0.150 173LSKLTQEQK 0.150 7 DLSVEVLAS 0.150 88 GVVTEDDEA 0.150 19 AWKCLGANI 0.12098 DSIDPPESP 0.100 145 GTLSLAFTS 0.100 83 QIPVVGVVT 0.100 8 LSVEVLASP0.100 168 LETIILSKL 0.100 169 ETIILSKLT 0.100 162 SGTWMKLET 0.100 11EVLASPAAA 0.100 25 ANILRGGLS 0.100 72 SGIRNKSSS 0.100 144 SGTLSLAFT0.100 140 SQAASGTLS 0.100 77 KSSSSSQIP 0.100 185 CMFSLISGS 0.100 20WKCLGANIL 0.100 95 EAQDSIDPP 0.060 111 KAANSWRNP 0.060 75 RNKSSSSSQ0.060 59 WTEEAGATA 0.060 1 PSIVILDLS 0.050 80 SSSQIPVVG 0.050 157GEFLGSGTW 0.050 33 SEIVLPIEW 0.050 161 GSGTWMKLE 0.050 114 NSWRNPVLP0.050 76 NKSSSSSQI 0.040 164 TWMKLETII 0.040 182 SKHCMFSLI 0.040 39IEWQQDRKI 0.040 58 MWTEEAGAT 0.030 89 VVTEDDEAQ 0.030

TABLE XXI V1-HLA-B3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 157 GPKDASRQVY 240.000 9 SPKSLSETCL60.000 250 IPIEIVNKTL 40.000 197 SAREIENLPL 27.000 323 LPMRRSERYL 20.000438 LPSIVILDLL 20.000 239 YARNQQSDFY 18.000 417 RAFEEEYYRF 18.000 379IPSVSNALNW 10.000 116 VSNNMRINQY 10.000 391 FSFIQSTLGY 10.000 220ISLATFFFLY 10.000 195 LSSAREIENL 7.500 137 FPDSLIVKGF 6.000 327RSERYLFLNM 6.000 262 VAITLLSLVY 6.000 361 ISFGIMSLGL 5.000 395QSTLGYVALL 5.000 267 LSLVYLAGLL 5.000 99 TSLWDLRHLL 5.000 127 ESNAEYLASL5.000 4 ISMMGSPKSL 5.000 382 VSNALNWREF 5.000 377 TSIPSVSNAL 5.000 428TPPNFVLALV 4.000 188 IPIDLGSLSS 4.000 111 KILIDVSNNM 4.000 181LARQLNFIPI 3.600 27 DARKVTVGVI 3.600 41 FAKSLTIRLI 3.600 384 NALNWREFSF3.000 312 FAMVHVAYSL 3.000 222 LATFFFLYSF 3.000 81 DALTKTNIIF 3.000 218VAISLATFFF 3.000 322 CLPMRRSERY 2.000 429 PPNFVLALVL 2.000 316HVAYSLCLPM 2.000 61 RNPKFASEFF 2.000 257 KTLPIVAITL 2.000 259 LPIVAITLLS2.000 45 LTIRLIRCGY 2.000 275 LLAAAYQLYY 2.000 274 GLLAAAYQLY 2.000 303KQLGLLSFFF 2.000 128 SNAEYLASLF 2.000 123 NQYPESNAEY 2.000 305LGLLSFFFAM 2.000 404 LISTFHVLIY 2.000 213 RGPVVVAISL 2.000 271YLAGLLAAAY 2.000 183 RQLNFIPIDL 2.000 214 GPVVVAISLA 2.000 134ASLFPDSLIV 1.500 440 SIVILDLLQL 1.500 98 YTSLWDLRHL 1.500 161 ASRQVYICSN1.500 285 GTKYRRFPPW 1.500 103 DLRHLLVGKI 1.200 336 MAYQQVHANI 1.200 255VNKTLPIVAI 1.200 65 FASEFFPHVV 1.200 49 LIRCGYHVVI 1.200 434 LALVLPSIVI1.200 133 LASLFPDSLI 1.200 24 GIKDARKVTV 1.200 241 RNQQSDFYKI 1.200 32TVGVIGSGDF 1.000 435 ALVLPSIVIL 1.000 273 AGLLAAAYQL 1.000 36 IGSGDFAKSL1.000 308 LSFFFAMVHV 1.000 56 VVIGSRNPKF 1.000 176 QQVIELARQL 1.000 296ETWLQCRKQL 1.000 43 KSLTIRLIRC 1.000 202 ENLPLRLFTL 1.000 147 NVVSAWALQL1.000 217 VVAISLATFF 1.000 216 VVVAISLATF 1.000 132 YLASLFPDSL 1.000 364GIMSLGLLSL 1.000 365 IMSLGLLSLL 1.000 92 AIHREHYTSL 1.000 314 MVHVAYSLCL1.000 410 VLIYGWKRAF 1.000 299 LQCRKQLGLL 1.000 394 IQSTLGYVAL 1.000 11KSLSETCLPN 1.000 263 AITLLSLVYL 1.000 172 IQARQQVIEL 1.000 219AISLATFFFL 1.000 298 WLQCRKQLGL 1.000 37 GSGDFAKSLT 1.000 402 ALLISTFHVL1.000 258 TLPIVAITLL 1.000 427 YTPPNFVLAL 1.000 139 DSLIVKGFNV 1.000 437VLPSIVILDL 1.000 266 LLSLVYLAGL 1.000

TABLE XXI V2-HLA-B3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 33 CPPPCPADFF 20.000 35 PPCPADFFLY6.000 14 SSGFTPFSCL 5.000 11 LSLSSGFTPF 5.000 2 GSPGLQALSL 5.000 20FSCLSLPSSW 2.500 34 PPPCPADFFL 2.000 3 SPGLQALSLS 2.000 22 CLSLPSSWDY2.000 32 RCPPPCPADF 2.000 18 TPFSCLSLPS 2.000 8 ALSLSLSSGF 1.000 9LSLSLSSGFT 0.500 13 LSSGFTPFSC 0.500 25 LPSSWDYRCP 0.300 4 PGLQALSLSL0.100 15 SGFTPFSCLS 0.100 27 SSWDYRCPPP 0.100 16 GFTPFSCLSL 0.100 6LQALSLSLSS 0.100 1 SGSPGLQALS 0.100 24 SLPSSWDYRC 0.100 36 PCPADFFLYF0.100 5 GLQALSLSLS 0.100 12 SLSSGFTPFS 0.100 23 LSLPSSWDYR 0.050 7QALSLSLSSG 0.030 30 DYRCPPPCPA 0.030 17 FTPFSCLSLP 0.010 10 SLSLSSGFTP0.010 21 SCLSLPSSWD 0.010 26 PSSWDYRCPP 0.005 28 SWDYRCPPPC 0.003 29WDYRCPPPCP 0.001 19 PFSCLSLPSS 0.001 31 YRCPPPCPAD 0.001

TABLE XXI V5A-HLA-B3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 1 ENLPLRLFTF 1.000 2 NLPLRLFTFW 0.5006 RLFTFWRGPV 0.400 8 FTFWRGPVVV 0.200 3 LPLRLFTFWR 0.200 10 FWRGPVVVAI0.120 7 LFTFWRGPVV 0.020 9 TFWRGPVVVA 0.010 4 PLRLFTFWRG 0.003 5LRLFTFWRGP 0.001

TABLE XXI V5B-HLA-3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 12 CSFADTQTEL 5.000 5 FSFIQIFCSF5.000 16 DTQTELELEF 1.000 14 FADTQTELEL 0.900 17 TQTELELEFV 0.600 22ELEFVFLLTL 0.300 18 QTELELEFVF 0.300 20 ELELEFVFLL 0.300 19 TELELEFVFL0.300 1 NWREFSFIQI 0.240 8 IQIFCSFADT 0.100 23 LEFVFLLTLL 0.100 24EFVFLLTLLL 0.100 2 WREFSFIQIF 0.030 3 REFSFIQIFC 0.020 21 LELEFVFLLT0.020 11 FCSFADTQTE 0.015 10 IFCSFADTQT 0.010 7 FIQIFCSFAD 0.010 4EFSFIQIFCS 0.010 9 QIFCSFADTQ 0.010 6 SFIQIFCSFA 0.010 13 SFADTQTELE0.002 15 ADTQTELELE 0.002

TABLE XXI V6-HLA-B3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 LPSIVILGKI 8.000 44 IPHVSPERVT2.000 46 HVSPERVTVM 2.000 6 IVILGKIILF 1.000 7 VILGKIILFL 1.000 5SIVILGKIIL 1.000 26 IKKGWEKSQF 0.450 9 LGKIILFLPC 0.300 35 FLEEGIGGTI0.240 43 TIPHVSPERV 0.200 11 KIILFLPCIS 0.200 27 KKGWEKSQFL 0.200 38EGIGGTIPHV 0.200 16 LPCISRKLKR 0.200 4 PSIVILGKII 0.200 32 KSQFLEEGIG0.150 19 ISRKLKRIKK 0.150 39 GIGGTIPHVS 0.100 14 LFLPCISRKL 0.100 21RKLKRIKKGW 0.100 25 RIKKGWEKSQ 0.060 22 KLKRIKKGWE 0.060 10 GKIILFLPCI0.040 28 KGWEKSQFLE 0.040 17 PCISRKLKRI 0.040 31 EKSQFLEEGI 0.040 24KRIKKGWEKS 0.020 34 QFLEEGIGGT 0.020 33 SQFLEEGIGG 0.015 13 ILFLPCISRK0.010 18 CISRKLKRIK 0.010 8 ILGKIILFLP 0.010 2 VLPSIVILGK 0.010 40IGGTIPHVSP 0.010 15 FLPCISRKLK 0.010 41 GGTIPHVSPE 0.010 1 LVLPSIVILG0.010 42 GTIPHVSPER 0.010 12 IILFLPCISR 0.010 45 PHVSPERVTV 0.003 20SRKLKRIKKG 0.003 30 WEKSQFLEEG 0.003 23 LKRIKKGWEK 0.003 37 EEGIGGTIPH0.001 36 LEEGIGGTIP 0.000 29 GWEKSQFLEE 0.000

TABLE XXI V7A-HLA-3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 SPKSLSETFL 60.000 1 GSPKSLSETF5.000 4 KSLSETFLPN 1.000 6 LSETFLPNGI 0.600 9 TFLPNGINGI 0.040 5SLSETFLPNG 0.020 10 FLPNGINGIK 0.010 7 SETFLPNGIN 0.010 8 ETFLPNGING0.010 3 PKSLSETFLP 0.000

TABLE XXI V7B-HLA-B3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 MAYQQSTLGY 6.000 9 QSTLGYVALL 5.0003 LNMAYQQSTL 1.000 8 QQSTLGYVAL 1.000 10 STLGYVALLI 0.400 7 YQQSTLGYVA0.100 2 FLNMAYQQST 0.100 6 AYQQSTLGYV 0.020 4 NMAYQQSTLG 0.010 1LFLNMAYQQS 0.010

TABLE XXI V7C-HLA-B3501- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 100 SIDPPESPDR 100.000 67 TAEAQESGIR9.000 33 LSEIVLPIEW 6.750 131 LWEFLLRLLK 4.500 91 VTEDDEAQDS 2.250 10SVEVLASPAA 1.800 52 STPPPPAMWT 1.250 6 ILDLSVEVLA 1.000 168 KLETIILSKL0.900 103 PPESPDRALK 0.900 127 GVGPLWEFLL 0.500 143 AASGTLSLAF 0.500 13VLASPAAAWK 0.400 51 LSTPPPPAMW 0.300 60 WTEEAGATAE 0.225 157 LGEFLGSGTW0.225 69 EAQESGIRNK 0.200 97 AQDSIDPPES 0.150 70 AQESGIRNKS 0.135 178TQEQKSKHCM 0.135 170 ETIILSKLTQ 0.125 128 VGPLWEFLLR 0.125 37 VLPIEWQQDR0.100 14 LASPAAAWKC 0.100 61 TEEAGATAEA 0.090 39 PIEWQQDRKI 0.090 162GSGTWMKLET 0.075 78 KSSSSSQIPV 0.075 160 FLGSGTWMKL 0.050 22 KCLGANILRG0.050 167 MKLETIILSK 0.050 38 LPIEWQQDRK 0.050 80 SSSSQIPVVG 0.030 79SSSSSQIPVV 0.030 83 SQIPVVGVVT 0.030 144 ASGTLSLAFT 0.030 81 SSSQIPVVGV0.030 146 GTLSLAFTSW 0.025 66 ATAEAQESGI 0.025 152 FTSWSLGEFL 0.025 125TNGVGPLWEF 0.025 92 TEDDEAQDSI 0.025 177 LTQEQKSKHC 0.025 21 WKCLGANILR0.025 106 SPDRALKAAN 0.025 94 DDEAQDSIDP 0.022 12 EVLASPAAAW 0.020 4IVILDLSVEV 0.020 173 ILSKLTQEQK 0.020 47 KIPPLSTPPP 0.020 113 AANSWRNPVL0.020 72 ESGIRNKSSS 0.015 43 QQDRKIPPLS 0.015 15 ASPAAAWKCL 0.015 140KSQAASGTLS 0.015 9 LSVEVLASPA 0.015 82 SSQIPVVGVV 0.015 155 WSLGEFLGSG0.015 105 ESPDRALKAA 0.015 148 LSLAFTSWSL 0.015 124 HTNGVGPLWE 0.013 129GPLWEFLLRL 0.013 31 GGLSEIVLPI 0.013 145 SGTLSLAFTS 0.013 185 HCMFSLISGS0.010 149 SLAFTSWSLG 0.010 65 GATAEAQESG 0.010 112 KAANSWRNPV 0.010 142QAASGTLSLA 0.010 25 GANILRGGLS 0.010 159 EFLGSGTWMK 0.010 23 CLGANILRGG0.010 109 RALKAANSWR 0.010 176 KLTQEQKSKH 0.010 35 EIVLPIEWQQ 0.010 175SKLTQEQKSK 0.010 18 AAAWKCLGAN 0.010 36 IVLPIEWQQD 0.010 5 VILDLSVEVL0.010 172 IILSKLTQEQ 0.010 156 SLGEFLGSGT 0.010 120 PVLPHTNGVG 0.010 147TLSLAFTSWS 0.010 89 GVVTEDDEAQ 0.010 153 TSWSLGEFLG 0.008 2 PSIVILDLSV0.008 141 SQAASGTLSL 0.007 150 LAFTSWSLGE 0.005 17 PAAAWKCLGA 0.005 101IDPPESPDRA 0.005 151 AFTSWSLGEF 0.005 117 WRNPVLPHTN 0.005 42 WQQDRKIPPL0.003 104 PESPDRALKA 0.003 24 LGANILRGGL 0.003 119 NPVLPHTNGV 0.003 118RNPVLPHTNG 0.003 102 DPPESPDRAL 0.003 53 TPPPPAMWTE 0.003 1 LPSIVILDLS0.003

TABLE VIII V8-HLA-A1- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 4 FLEEGMGGT 0.900 5 LEEGMGGTI 0.0451 KSQFLEEGM 0.015 7 EGMGGTIPH 0.013 8 GMGGTIPHV 0.010 9 MGGTIPHVS 0.0033 QFLEEGMGG 0.003 2 SQFLEEGMG 0.002 6 EEGMGGTIP 0.000

TABLE VIII V13-HLA-A1- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 5 LSETFLPNG 2.700 4 SLSETFLPN 0.0507 ETFLPNGIN 0.025 8 TFLPNGING 0.025 9 FLPNGINGI 0.010 3 KSLSETFLP 0.0071 SPKSLSETF 0.003 6 SETFLPNGI 0.001 2 PKSLSETFL 0.000

TABLE VIII V14-HLA-A1- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 NLPLRLFTF 0.500 7 FTFWRGPVV 0.0503 PLRLFTFWR 0.005 5 RLFTFWRGP 0.001 6 LFTFWRGPV 0.001 4 LRLFTFWRG 0.0012 LPLRLFTFW 0.000 9 FWRGPVVVA 0.000 8 TFWRGPVVV 0.000

TABLE VIII V21-HLA-A1- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 KLTQEQKTK 0.200 4 TQEQKTKHC 0.1353 LTQEQKTKH 0.025 8 KTKHCMFSL 0.013 6 EQKTKHCMF 0.002 9 TKHCMFSLI 0.0011 SKLTQEQKT 0.001 7 QKTKHCMFS 0.000 5 QEQKTKHCM 0.000

TABLE VIII V25-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 LFLPCISQK 0.100 1 ILFLPCISQ 0.0505 PCISQKLKR 0.050 4 LPCISQKLK 0.050 7 ISQKLKRIK 0.030 8 SQKLKRIKK 0.0153 FLPCISQKL 0.010 6 CISQKLKRI 0.010 9 QKLKRIKKG 0.000

TABLE IX V8-HLA-A1- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 FLEEGMGGTI 0.900 2 KSQFLEEGMG 0.0153 SQFLEEGMGG 0.007 8 EGMGGTIPHV 0.005 9 GMGGTIPHVS 0.005 6 LEEGMGGTIP0.005 7 EEGMGGTIPH 0.003 4 QFLEEGMGGT 0.001 10 MGGTIPHVSP 0.001 1EKSQFLEEGM 0.001

TABLE IX V13-HLA-A1- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 6 LSETFLPNGI 1.350 10 FLPNGINGIK0.200 8 ETFLPNGING 0.125 4 KSLSETFLPN 0.075 5 SLSETFLPNG 0.020 1GSPKSLSETF 0.015 9 TFLPNGINGI 0.005 7 SETFLPNGIN 0.001 2 SPKSLSETFL0.000 3 PKSLSETFLP 0.000

TABLE IX V14-HLA-A1- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 1 ENLPLRLFTF 1.250 8 FTFWRGPVVV 0.0503 LPLRLFTFWR 0.013 2 NLPLRLFTFW 0.010 6 RLFTFWRGPV 0.010 7 LFTFWRGPVV0.001 4 PLRLFTFWRG 0.000 10 FWRGPVVVAI 0.000 5 LRLFTFWRGP 0.000 9TFWRGPVVVA 0.000

TABLE IX V21-HLA-A1- 10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 TQEQKTKHCM 0.135 4 LTQEQKTKHC 0.0253 KLTQEQKTKH 0.010 2 SKLTQEQKTK 0.010 9 KTKHCMFSLI 0.003 10 TKHCMFSLIS0.003 1 LSKLTQEQKT 0.002 7 EQKTKHCMFS 0.001 6 QEQKTKHCMF 0.001 8QKTKHCMFSL 0.000

TABLE IX V25-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 7 CISQKLKRIK 0.200 4 FLPCISQKLK 0.2002 ILFLPCISQK 0.200 8 ISQKLKRIKK 0.150 5 LPCISQKLKR 0.125 1 IILFLPCISQ0.050 3 LFLPCISQKL 0.005 6 PCISQKLKRI 0.001 9 SQKLKRIKKG 0.000 10QKLKRIKKGW 0.000

TABLE X V8-A0201-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:17; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Start Subsequence Score 8 GMGGTIPHV 115.534 4 FLEEGMGGT 2.689 1KSQFLEEGM 0.056 2 SQFLEEGMG 0.004 5 LEEGMGGTI 0.003 3 QFLEEGMGG 0.001 9MGGTIPHVS 0.000 7 EGMGGTIPH 0.000 6 EEGMGGTIP 0.000

TABLE X V13-A0201-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:27; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Start Subsequence Score 9 FLPNGINGI 110.379 4 SLSETFLPN 0.581 6SETFLPNGI 0.203 3 KSLSETFLP 0.007 2 PKSLSETFL 0.004 5 LSETFLPNG 0.000 8TFLPNGING 0.000 7 ETFLPNGIN 0.000 1 SPKSLSETF 0.000

TABLE X V14-A0201-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:29; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Start Subsequence Score 7 FTFWRGPVV 6.741 1 NLPLRLFTF 0.994 8TFWRGPVVV 0.164 5 RLFTFWRGP 0.071 2 LPLRLFTFW 0.032 6 LFTFWRGPV 0.011 3PLRLFTFWR 0.003 4 LRLFTFWRG 0.001 9 FWRGPVVVA 0.000

TABLE X V21-A0201-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:43; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Start Subsequence Score 8 KTKHCMFSL 0.485 5 QEQKTKHCM 0.097 2KLTQEQKTK 0.052 1 SKLTQEQKT 0.038 4 TQEQKTKHC 0.032 9 TKHCMFSLI 0.028 3LTQEQKTKH 0.007 7 QKTKHCMFS 0.001 6 EQKTKHCMF 0.000

TABLE X V25-A0201-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:51; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Start Subsequence Score 3 FLPCISQKL 98.267 6 CISQKLKRI 3.299 1ILFLPCISQ 0.094 9 QKLKRIKKG 0.001 4 LPCISQKLK 0.000 2 LFLPCISQK 0.000 8SQKLKRIKK 0.000 7 ISQKLKRIK 0.000 5 PCISQKLKR 0.000

TABLE X V8-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 FLEEGMGGTI 1.637 8 EGMGGTIPHV 0.2903 SQFLEEGMGG 0.028 4 QFLEEGMGGT 0.023 9 GMGGTIPHVS 0.022 1 EKSQFLEEGM0.000 2 KSQFLEEGMG 0.000 10 MGGTIPHVSP 0.000 7 EEGMGGTIPH 0.000 6LEEGMGGTIP 0.000

TABLE X V-13-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 SLSETFLPNG 2.670 9 TFLPNGINGI 0.0622 SPKSLSETFL 0.027 4 KSLSETFLPN 0.012 6 LSETFLPNGI 0.007 10 FLPNGINGIK0.004 8 ETFLPNGING 0.000 1 GSPKSLSETF 0.000 7 SETFLPNGIN 0.000 3PKSLSETFLP 0.000

TABLE X V14-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 6 RLFTFWRGPV 33.455 8 FTFWRGPVVV6.741 2 NLPLRLFTFW 0.779 3 LPLRLFTFWR 0.074 7 LFTFWRGPVV 0.034 9TFWRGPVVVA 0.027 1 ENLPLRLFTF 0.002 4 PLRLFTFWRG 0.002 10 FWRGPVVVAI0.001 5 LRLFTFWRGP 0.000

TABLE X V21-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 TQEQKTKHCM 0.135 4 LTQEQKTKHC 0.0253 KLTQEQKTKH 0.010 2 SKLTQEQKTK 0.010 9 KTKHCMFSLI 0.003 10 TKHCMFSLIS0.003 1 LSKLTQEQKT 0.002 7 EQKTKHCMFS 0.001 6 QEQKTKHCMF 0.001 8QKTKHCMFSL 0.000

TABLE X V25-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 ILFLPCISQK 0.216 3 LFLPCISQKL 0.0934 FLPCISQKLK 0.069 1 IILFLPCISQ 0.013 6 PCISQKLKRI 0.003 9 SQKLKRIKKG0.001 10 QKLKRIKKGW 0.000 7 CISQKLKRIK 0.000 8 ISQKLKRIKK 0.000 5LPCISQKLKR 0.000

TABLE XII V8-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:43; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Start Subsequence Score 8 GMGGTIPHV 1.350 4 FLEEGMGGT 0.068 1KSQFLEEGM 0.003 2 SQFLEEGMG 0.001 5 LEEGMGGTI 0.001 7 EGMGGTIPH 0.000 3QFLEEGMGG 0.000 9 MGGTIPHVS 0.000 6 EEGMGGTIP 0.000

TABLE XII V13-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 FLPNGINGI 0.900 4 SLSETFLPN 0.1801 SPKSLSETF 0.020 1 SETFLPNGI 0.002 3 KSLSETFLP 0.001 7 ETFLPNGIN 0.0015 LSETFLPNG 0.000 8 TFLPNGING 0.000 2 PKSLSETFL 0.000

TABLE XII V14-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 NLPLRLFTF 9.000 3 PLRLFTFWR 3.6007 FTFWRGPVV 0.050 5 RLFTFWRGP 0.030 2 LPLRLFTFW 0.009 9 FWRGPVVVA 0.0018 TFWRGPVVV 0.001 4 LRLFTFWRG 0.000 6 LFTFWRGPV 0.000

TABLE XII V21-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 KLTQEQKTK 30.000 8 KTKHCMFSL 0.4056 EQKTKHCMF 0.018 3 LTQEQKTKH 0.015 4 TQEQKTKHC 0.003 9 TKHCMFSLI 0.0025 QEQKTKHCM 0.001 1 SKLTQEQKT 0.000 7 QKTKHCMFS 0.000

TABLE XII V25-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 8 SQKLKRIKK 1.200 3 FLPCISQKL 0.9001 ILFLPCISQ 0.300 4 LPCISQKLK 0.100 2 LFLPCISQK 0.068 6 CISQKLKRI 0.0455 PCISQKLKR 0.012 7 ISQKLKRIK 0.010 9 QKLKRIKKG 0.000

TABLE XIII V8-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 9 GMGGTIPHVS 0.270 5 FLEEGMGGTI 0.2703 SQFLEEGMGG 0.006 7 EEGMGGTIPH 0.000 8 EGMGGTIPHV 0.000 4 QFLEEGMGGT0.000 6 LEEGMGGTIP 0.000 2 KSQFLEEGMG 0.000 1 EKSQFLEEGM 0.000 10MGGTIPHVSP 0.000

TABLE XIII V13-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 10 FLPNGINGIK 9.000 5 SLSETFLPNG0.135 1 GSPKSLSETF 0.030 2 SPKSLSETFL 0.006 6 LSETFLPNGI 0.003 8ETFLPNGING 0.003 4 KSLSETFLPN 0.003 9 TFLPNGINGI 0.002 7 SETFLPNGIN0.000 3 PKSLSETFLP 0.000

TABLE XIII V14-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 6 RLFTFWRGPV 0.900 2 NLPLRLFTFW 0.6003 LPLRLFTFWR 0.540 6 FTFWRGPVVV 0.050 4 PLRLFTFWRG 0.018 1 ENLPLRLFTF0.012 9 TFWRGPVVVA 0.005 10 FWRGPVVVAI 0.004 7 LFTFWRGPVV 0.000 5LRLFTFWRGP 0.000

TABLE XIII V21-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 KLTQEQKTKH 0.600 9 KTKHCMFSLI 0.2702 SKLTQEQKTK 0.015 4 LTQEQKTKHC 0.007 6 QEQKTKHCMF 0.006 5 TQEQKTKHCM0.006 8 QKTKHCMFSL 0.003 7 EQKTKHCMFS 0.001 1 LSKLTQEQKT 0.001 10 TKHCMFSLIS 0.000

TABLE XIII V25-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 ILFLPCISQK 150.000 4 FLPCISQKLK10.000 8 ISQKLKRIKK 0.200 7 CISQKLKRIK 0.200 5 LPCISQKLKR 0.080 1IILFLPCISQ 0.009 3 LFLPCISQKL 0.002 6 PCISQKLKRI 0.001 9 SQKLKRIKKG0.000 10  QKLKRIKKGW 0.000

TABLE XIV V8-HLA-A1101-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 8 GMGGTIPHV 1.350 4 FLEEGMGGT 0.0681 KSQFLEEGM 0.003 2 SQFLEEGMG 0.001 5 LEEGMGGTI 0.001 7 EGMGGTIPH 0.0003 QFLEEGMGG 0.000 9 MGGTIPHVS 0.000 6 EEGMGGTIP 0.000

TABLE XIV V13-HLA-A1101-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 FLPNGINGI 0.004 1 SPKSLSETF 0.0024 SLSETFLPN 0.001 7 ETFLPNGIN 0.001 8 TFLPNGING 0.001 6 SETFLPNGI 0.0013 KSLSETFLP 0.000 2 PKSLSETFL 0.000 5 LSETFLPNG 0.000

TABLE XIV V14-HLA-A1101-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 3 PLRLFTFWR 0.024 7 FTFWRGPVV 0.0201 NLPLRLFTF 0.012 8 TFWRGPVVV 0.004 2 LPLRLFTFW 0.003 6 LFTFWRGPV 0.0025 RLFTFWRGP 0.000 9 FWRGPVVVA 0.000 4 LRLFTFWRG 0.000

TABLE XIV V21-HLA-A1101-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 KLTQEQKTK 0.600 8 KTKHCMFSL 0.0903 LTQEQKTKH 0.010 6 EQKTKHCMF 0.002 5 QEQKTKHCM 0.001 4 TQEQKTKHC 0.0009 TKHCMFSLI 0.000 7 QKTKHCMFS 0.000 1 SKLTQEQKT 0.000

TABLE XIV V25-HLA-A1101-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 8 SQKLKRIKK 1.200 2 LFLPCISQK 0.3004 LPCISQKLK 0.100 5 PCISQKLKR 0.012 3 FLPCISQKL 0.004 7 ISQKLKRIK 0.0026 CISQKLKRI 0.002 1 ILFLPCISQ 0.002 9 QKLKRIKKG 0.000

TABLE XV V8-HLA-A11-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 FLEEGMGGTI 0.004 3 SQFLEEGMGG 0.0029 GMGGTIPHVS 0.001 7 EEGMGGTIPH 0.000 4 QFLEEGMGGT 0.000 8 EGMGGTIPHV0.000 2 KSQFLEEGMG 0.000 6 LEEGMGGTIP 0.000 1 EKSQFLEEGM 0.000 10 MGGTIPHVSP 0.000

TABLE XV V13-HLA-A11-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 10  FLPNGINGIK 0.400 9 TFLPNGINGI0.003 2 SPKSLSETFL 0.002 8 ETFLPNGING 0.001 1 GSPKSLSETF 0.001 5SLSETFLPNG 0.000 6 LSETFLPNGI 0.000 4 KSLSETFLPN 0.000 7 SETFLPNGIN0.000 3 PKSLSETFLP 0.000

TABLE XV V14-HLA-A11-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 LPLRLFTFWR 0.180 6 RLFTFWRGPV 0.0248 FTFWRGPVVV 0.020 9 TFWRGPVVVA 0.004 2 NLPLRLFTFW 0.004 7 LFTFWRGPVV0.002 1 ENLPLRLFTF 0.001 10  FWRGPVVVAI 0.000 4 PLRLFTFWRG 0.000 5LRLFTFWRGP 0.000

TABLE XV V21-HLA-A11-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 KTKHCMFSLI 0.030 2 SKLTQEQKTK0.015 3 KLTQEQKTKH 0.012 5 TQEQKTKHCM 0.006 8 QKTKHCMFSL 0.001 6QEQKTKHCMF 0.001 4 LTQEQKTKHC 0.001 7 EQKTKHCMFS 0.000 10  TKHCMFSLIS0.000 1 LSKLTQEQKT 0.000

TABLE XV V25-HLA-A11-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 ILFLPCISQK 0.800 4 FLPCISQKLK 0.2005 LPCISQKLKR 0.080 8 ISQKLKRIKK 0.040 7 CISQKLKRIK 0.040 3 LFLPCISQKL0.040 1 IILFLPCISQ 0.001 9 SQKLKRIKKG 0.000 10  QKLKRIKKGW 0.000 6PCISQKLKRI 0.000

TABLE XVI V8-HLA-A24-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 KSQFLEEGM 1.800 4 FLEEGMGGT 0.1805 LEEGMGGTI 0.150 9 MGGTIPHVS 0.140 8 GMGGTIPHV 0.100 3 QFLEEGMGG 0.0907 EGMGGTIPH 0.015 2 SQFLEEGMG 0.010 6 EEGMGGTIP 0.001

TABLE XVI V13-HLA-A24-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 SPKSLSETF 2.400 9 FLPNGINGI 1.8004 SLSETFLPN 0.144 6 SETFLPNGI 0.144 7 ETFLPNGIN 0.100 8 TFLPNGING 0.0902 PKSLSETFL 0.040 3 KSLSETFLP 0.030 5 LSETFLPNG 0.015

TABLE XVI V14-HLA-A24-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 NLPLRLFTF 3.000 8 TFWRGPVVV 0.5006 LFTFWRGPV 0.500 2 LPLRLFTFW 0.216 7 FTFWRGPVV 0.100 9 FWRGPVVVA 0.1005 RLFTFWRGP 0.020 4 LRLFTFWRG 0.002 3 PLRLFTFWR 0.001

TABLE XVI V21-HLA-A24-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 8 KTKHCMFSL 8.000 6 EQKTKHCMF 2.0004 TQEQKTKHC 0.150 9 TKHCMFSLI 0.120 5 QEQKTKHCM 0.075 2 KLTQEQKTK 0.0201 SKLTQEQKT 0.020 3 LTQEQKTKH 0.020 7 QKTKHCMFS 0.010

TABLE XVI V25-HLA-A24-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 3 FLPCISQKL 11.088 6 CISQKLKRI 1.0002 LFLPCISQK 0.090 7 ISQKLKRIK 0.018 8 SQKLKRIKK 0.011 1 ILFLPCISQ 0.0104 LPCISQKLK 0.010 9 QKLKRIKKG 0.002 5 PCISQKLKR 0.002

TABLE XVII V8-HLA-A24-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 FLEEGMGGTI 1.800 4 QFLEEGMGGT 0.9008 EGMGGTIPHV 0.150 9 GMGGTIPHVS 0.140 1 EKSQFLEEGM 0.060 2 KSQFLEEGMG0.030 10  MGGTIPHVSP 0.010 3 SQFLEEGMGG 0.010 6 LEEGMGGTIP 0.002 7EEGMGGTIPH 0.001

TABLE XVII V13-HLA-A24-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 9 TFLPNGINGI 10.800 2 SPKSLSETFL4.000 1 GSPKSLSETF 3.600 6 LSETFLPNGI 2.160 4 KSLSETFLPN 0.360 10 FLPNGINGIK 0.021 5 SLSETFLPNG 0.012 7 SETFLPNGIN 0.010 8 ETFLPNGING0.010 3 PKSLSETFLP 0.000

TABLE XVII V14-HLA-A24-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 1 ENLPLRLFTF 3.600 10  FWRGPVVVAI1.400 7 LFTFWRGPVV 0.500 9 TFWRGPVVVA 0.500 2 NLPLRLFTFW 0.216 6RLFTFWRGPV 0.200 8 FTFWRGPVVV 0.100 3 LPLRLFTFWR 0.015 5 LRLFTFWRGP0.002 4 PLRLFTFWRG 0.001

TABLE XVII V21-HLA-A24-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 9 KTKHCMFSLI 2.400 5 TQEQKTKHCM 0.7508 QKTKHCMFSL 0.400 6 QEQKTKHCMF 0.300 4 LTQEQKTKHC 0.180 1 LSKLTQEQKT0.132 7 EQKTKHCMFS 0.100 3 KLTQEQKTKH 0.022 10  TKHCMFSLIS 0.010 2SKLTQEQKTK 0.002

TABLE XVII V25-HLA-A24-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 LFLPCISQKL 66.528 6 PCISQKLKRI0.150 10  QKLKRIKKGW 0.021 8 ISQKLKRIKK 0.017 4 FLPCISQKLK 0.015 1IILFLPCISQ 0.015 7 CISQKLKRIK 0.012 9 SQKLKRIKKG 0.011 5 LPCISQKLKR0.011 2 ILFLPCISQK 0.010

TABLE XVIII V8-HLA-B7-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 KSQFLEEGM 1.000 8 GMGGTIPHV 0.2007 EGMGGTIPH 0.030 4 FLEEGMGGT 0.030 9 MGGTIPHVS 0.020 5 LEEGMGGTI 0.0122 SQFLEEGMG 0.010 6 EEGMGGTIP 0.001 3 QFLEEGMGG 0.001

TABLE XVIII V13-HLA-B7-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 0amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 9 FLPNGINGI 0.400 1 SPKSLSETF 0.4006 SETFLPNGI 0.040 2 PKSLSETFL 0.040 7 ETFLPNGIN 0.030 4 SLSETFLPN 0.0203 KSLSETFLP 0.010 5 LSETFLPNG 0.003 8 TFLPNGING 0.001

TABLE XVIII V14-HLA-B7-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 LPLRLFTFW 0.400 7 FTFWRGPVV 0.2009 FWRGPVVVA 0.150 6 LFTFWRGPV 0.030 8 TFWRGPVVV 0.020 1 NLPLRLFTF 0.0203 PLRLFTFWR 0.010 5 RLFTFWRGP 0.010 4 LRLFTFWRG 0.001

TABLE XVIII V21-HLA-B7-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 8 KTKHCMFSL 4.000 5 QEQKTKHCM 0.1009 TKHCMFSLI 0.040 4 TQEQKTKHC 0.030 6 EQKTKHCMF 0.020 3 LTQEQKTKH 0.0101 SKLTQEQKT 0.010 2 KLTQEQKTK 0.010 7 QKTKHCMFS 0.002

TABLE XVIII V25-HLA-B7-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 3 FLPCISQKL 4.000 6 CISQKLKRI 0.4004 LPCISQKLK 0.200 8 SQKLKRIKK 0.015 1 ILFLPCISQ 0.015 7 ISQKLKRIK 0.0109 QKLKRIKKG 0.001 2 LFLPCISQK 0.001 5 PCISQKLKR 0.001

TABLE XIX V8-HLA-B7-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 9 EGMGGTIPHV 0.600 5 FLEEGMGGTI 0.1201 EKSQFLEEGM 0.100 9 GMGGTIPHVS 0.020 10  MGGTIPHVSP 0.015 4 QFLEEGMGGT0.010 3 SQFLEEGMGG 0.010 2 KSQFLEEGMG 0.010 7 EEGMGGTIPH 0.001 6LEEGMGGTIP 0.000

TABLE XIX V13-HLA-B7-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 SPKSLSETFL 80.000 6 LSETFLPNGI0.120 9 TFLPNGINGI 0.040 1 GSPKSLSETF 0.020 4 KSLSETFLPN 0.020 10 FLPNGINGIK 0.010 5 SLSETFLPNG 0.010 8 ETFLPNGING 0.010 7 SETFLPNGIN0.003 3 PKSLSETFLP 0.000

TABLE XIX V14-HLA-B7-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 10  FWRGPVVVAI 0.400 6 RLFTFWRGPV0.300 8 FTFWRGPVVV 0.200 3 LPLRLFTFWR 0.200 2 NLPLRLFTFW 0.020 7LFTFWRGPVV 0.020 1 ENLPLRLFTF 0.020 9 TFWRGPVVVA 0.015 4 PLRLFTFWRG0.010 5 LRLFTFWRGP 0.001

TABLE XIX V21-HLA-B7-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 9 KTKHCMFSLI 0.400 8 QKTKHCMFSL 0.4005 TQEQKTKHCM 0.300 1 LSKLTQEQKT 0.100 4 LTQEQKTKHC 0.100 7 EQKTKHCMFS0.020 3 KLTQEQKTKH 0.010 10  TKHCMFSLIS 0.002 6 QEQKTKHCMF 0.002 2SKLTQEQKTK 0.001

TABLE XIX V25-HLA-B7-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 3 LFLPCISQKL 0.400 5 LPCISQKLKR 0.2006 PCISQKLKRI 0.040 8 ISQKLKRIKK 0.015 1 IILFLPCISQ 0.015 7 CISQKLKRIK0.010 4 FLPCISQKLK 0.010 9 SQKLKRIKKG 0.010 2 ILFLPCISQK 0.010 10 QKLKRIKKGW 0.002

TABLE XX V8-HLA-B3501-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 KSQFLEEGM 20.000 8 GMGGTIPHV 0.2009 MGGTIPHVS 0.100 4 FLEEGMGGT 0.060 2 SQFLEEGMG 0.015 5 LEEGMGGTI 0.0127 EGMGGTIPH 0.010 3 QFLEEGMGG 0.003 6 EEGMGGTIP 0.001

TABLE XX V13-HLA-B3501-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 1 SPKSLSETF 60.000 9 FLPNGINGI 0.4004 SLSETFLPN 0.200 3 KSLSETFLP 0.150 7 ETFLPNGIN 0.100 6 SETFLPNGI 0.0405 LSETFLPNG 0.015 2 PKSLSETFL 0.010 8 TFLPNGING 0.001

TABLE XX V14-HLA-B3501-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 2 LPLRLFTFW 10.000 1 NLPLRLFTF 1.0007 FTFWRGPVV 0.200 9 FWRGPVVVA 0.030 6 LFTFWRGPV 0.020 5 RLFTFWRGP 0.0208 TFWRGPVVV 0.020 3 PLRLFTFWR 0.003 4 LRLFTFWRG 0.001

TABLE XX V21-HLA-B3501-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 8 KTKHCMFSL 6.000 6 EQKTKHCMF 3.0005 QEQKTKHCM 0.200 9 TKHCMFSLI 0.040 2 KLTQEQKTK 0.030 4 TQEQKTKHC 0.0303 LTQEQKTKH 0.020 7 QKTKHCMFS 0.010 1 SKLTQEQKT 0.010

TABLE XX V25-HLA-B3501-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Start Subsequence Score 3 FLPCISQKL 1.000 6 CISQKLKRI 0.4004 LPCISQKLK 0.200 7 ISQKLKRIK 0.050 8 SQKLKRIKK 0.030 1 ILFLPCISQ 0.0109 QKLKRIKKG 0.001 2 LFLPCISQK 0.001 5 PCISQKLKR 0.001

TABLE XXI V8-HLA-B35-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 FLEEGMGGTI 0.240 8 EGMGGTIPHV 0.2001 EKSQFLEEGM 0.200 2 KSQFLEEGMG 0.150 9 GMGGTIPHVS 0.100 4 QFLEEGMGGT0.020 3 SQFLEEGMGG 0.015 10  MGGTIPHVSP 0.010 7 EEGMGGTIPH 0.001 6LEEGMGGTIP 0.000

TABLE XXI V13-HLA-B35-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 2 SPKSLSETFL 60.000 1 GSPKSLSETF5.000 4 KSLSETFLPN 1.000 6 LSETFLPNGI 0.600 9 TFLPNGINGI 0.040 5SLSETFLPNG 0.020 10  FLPNGINGIK 0.010 7 SETFLPNGIN 0.010 8 ETFLPNGING0.010 3 PKSLSETFLP 0.000

TABLE XXI V14-HLA-B35-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 1 ENLPLRLFTF 1.000 2 NLPLRLFTFW 0.5006 RLFTFWRGPV 0.400 8 FTFWRGPVVV 0.200 3 LPLRLFTFWR 0.200 10  FWRGPVVVAI0.120 7 LFTFWRGPVV 0.020 9 TFWRGPVVVA 0.010 4 PLRLFTFWRG 0.003 5LRLFTFWRGP 0.001

TABLE XXI V21-HLA-B35-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 9 KTKHCMFSLI 2.400 1 LSKLTQEQKT 1.5005 TQEQKTKHCM 0.600 7 EQKTKHCMFS 0.300 4 LTQEQKTKHC 0.200 6 QEQKTKHCMF0.100 8 QKTKHCMFSL 0.100 3 KLTQEQKTKH 0.020 10 TKHCMFSLIS 0.010 2SKLTQEQKTK 0.002

TABLE XXI V25-HLA-B35-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Start Subsequence Score 5 LPCISQKLKR 0.200 3 LFLPCISQKL 0.1008 ISQKLKRIKK 0.050 10 QKLKRIKKGW 0.050 6 PCISQKLKRI 0.040 9 SQKLKRIKKG0.030 4 FLPCISQKLK 0.010 7 CISQKLKRIK 0.010 2 ILFLPCISQK 0.010 1IILFIPCISQ 0.010

TABLE XXII V1-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 158 PKDASRQVY 27 419 FEEEYYRFY 27 405ISTFHVLIY 26 221 SLATFEFLY 23 263 AITLLSLVY 23 392 SEIQSTLGY 23 276LAAAYQLYY 22 280 YQLYYGTKY 21 244 QSDFYKIPI 19 101 LWDLRHLLV 18 189PIDLGSLSS 18 198 AREIENLPL 18 231 FVRDVIIPY 18 240 ARNQQSDFY 18 275LLAAAYQLY 18 311 FFAMVHVAY 18 90 FVAIHREHY 17 117 SNNMRINQY 17 327RSERYLFLN 17 388 WREFSFIQS 17 427 YTPPNFVLA 17 443 ILDLLQLCR 17 444LDLLQLCRY 17 46 TIRLIRCGY 16 66 ASEFFPHVV 16 124 QYPESNAEY 16 200EIENLPLRI 16 330 RYLFLNMAY 16 352 EEVWRIEMY 16 272 LAGLLAAAY 15 323LPMRRSERY 15 351 EEEVWRIEM 15 415 WKRAFEEEY 15 416 KRAFEEEYY 15 13LSETCLPNG 14 38 SGDFAKSLT 14 98 YTSLWDLRH 14 178 VIELARQLN 14 406STFHVLIYG 14 94 HREHYTSLW 13 135 SLFPDSLIV 13 137 FPDSLIVKG 13 251PIEIVNKTL 13 396 STLGYVALL 13

TABLE XXII V2-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 23 LSLPSSWDY 23 36 PCPADFFLY 20 17FTPFSCLSL 13 28 SWDYRCPPP 12

TABLE XXII V5A-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 FTFWRGPVV 9 9 FWRGPVVVA 5

TABLE XXII V5B-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 21 ELEFVELLT 24 1 WREFSFIQI 17 17QTELELEFV 16 13 FADTQTELE 15 19 ELELEFVFL 14

TABLE XXII V6-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 34 FLEEGIGGT 14 28 GWEKSQFLE 12 35LEEGIGGTI 12 29 WEKSQFLEE 11 41 GTIPHVSPE 11 1 VLPSIVILG 9 9 GKIILFLPC 919 SRKLKRIKK 9 2 LPSIVILGK 8 0 6 VILGKIILF 8 16 PCISRKLKR 8 7 ILGKIILFL7 37 EGIGGTIPH 7 46 VSPERVTVM 7 3 PSIVILGKI 6 5 IVILGKIIL 6 12 ILFLPCISR6

TABLE XXII V7A-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 LSETFLPNG 14 4 SLSETFLPN 12 8TFLPNGING 9 7 ETFLPNGIN 8 3 KSLSETFLP 6

TABLE XXII V7B-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 AYQQSTLGY 22 9 STLGYVALL 13

TABLE XXII V7C-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 59 WTEEAGATA 17 90 VTEDDEAQD 17 99SIDPPESPD 17 167 KLETIILSK 17 32 LSEIVLPIE 16 51 STPPPPAMW 14 154WSLGEFLGS 14 5 ILDLSVEVL 13 69 AQESGIRNK 13 9 SVEVLASPA 12 38 PIEWQQDRK12 60 TEEAGATAE 12 66 TAEAQESGI 12 93 DDEAQDSID 12 104 ESPDRALKA 12 105SPDRALKAA 12 123 HTNGVGPLW 12 130 LWEFLLRLL 12 96 AQDSIDPPE 11 102PPESPDRAL 11 128 GPLWEFLLR 11 143 ASGTLSLAF 11 156 LGEFLGSGT 11 42QQDRKIPPL 10 78 SSSSSQIPV 10 82 SQIPVVGVV 10 91 TEDDEAQDS 10 92EDDEAQDSI 10 115 SWRNPVLPH 10 176 LTQEQKSKH 10 177 TQEQKSKHC 10 26NILRGGLSE 9 50 LSTPPPPAM 9 79 SSSSQIPVV 9 131 WEFLLRLLK 9 2 SIVILDLSV 87 DLSVEVLAS 8 21 KCLGANILR 8 31 GLSEIVLPI 8 81 SSQIPVVGV 8 124 TNGVGPLWE8 132 EFLLRLLKS 8 141 QAASGTLSL 8 162 SGTWMKLET 8 169 ETIILSKLT 8

TABLE XXII V8-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 FLEEGMGGT 14 5 LEEGMGGTI 12 7EGMGGTIPH 7

TABLE XXII V13-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 LSETFLPNG 14 4 SLSETFLPN 12 8TFLPNGING 9 7 ETFLPNGIN 8 3 KSLSETFLP 6

TABLE XXII V14-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 FTFWRGPVV 9 9 FWRGPVVVA 5

TABLE XXII V21-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 LTQEQKTKH 10 4 TQEQKTKHC 10 1SKLTQEQKT 6 8 KTKHCMFSL 6 9 TKHCMFSLI 5

TABLE XXII V25-HLA-A1-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 PCISQKLKR 10 8 SQKLKRIKK 9 1 ILFLPCISQ6 2 LFLPCISQK 4 3 FLPCISQKL 4 7 ISQKLKRIK 4

TABLE XXIII V1-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 365 IMSLGLLSL 29 271 YLAGLLAAA 28 433VLALVLPSI 28 227 FLYSFVRDV 27 360 YISFGIMSL 27 396 STLGYVALL 27 17CLPNGINGI 26 100 SLWDLRHLL 26 135 SLFPDSLIV 26 203 NLPLRLFTL 26 402ALLISTFHV 26 436 LVLPSIVIL 26 128 SNAEYLASL 25 140 SLIVKGENV 25 187FIPIDLGSL 25 210 TLWRGPVVV 25 261 IVAITLLSL 25 403 LLISTFHVL 25 5SMMGSPKSL 24 264 ITLLSLVYL 24 274 GLLAAAYQL 24 307 LLSFFFAMV 24 369GLLSLLAVT 24 48 RLIRCGYHV 23 49 LIRCGYHVV 23 141 LIVKGFNVV 23 313AMVHVAYSL 23 374 LAVTSIPSV 23 393 FIQSTLGYV 23 441 IVILDLLQL 23 106HLLVGKILI 22 180 ELARQLNFI 22 254 IVNKTLPIV 22 258 TLPIVAITL 22 262VAITLLSLV 22 265 TLLSLVYLA 22 267 LSLVYLAGL 22 268 SLVYLAGLL 22 333FLNMAYQQV 22 378 SIPSVSNAL 22 404 LISTFHVLI 21 435 ALVLPSIVI 21 107LLVGKILID 20 108 LVGKILIDV 20 112 ILIDVSNNM 20 173 QARQQVIEL 20 184QLNFIPIDL 20 368 LGLLSLLAV 20 65 FASEFFPHV 19 83 LTKTNIIFV 19 133LASLFPDSL 19 177 QVIELARQL 19 257 KTLPIVAIT 19 306 GLLSFFFAM 19 366MSLGLLSLL 19 434 LALVLPSIV 19 27 DARKVTVGV 18 196 SSAREIENL 18 209FTLWRGPVV 18 259 LPIVAITLL 18 367 SLGLLSLLA 18 371 LSLLAVTSI 18 397TLGYVALLI 18 41 FAKSLTIRL 17 81 DALTKTNII 17 85 KTNIIFVAI 17 103DLRHLLVGK 17 104 LRHLLVGKI 17 153 ALQLGPKDA 17 155 QLGPKDASR 17 212WRGPVVVAI 17 250 IPIEIVNKT 17 253 EIVNKTLPI 17 363 FGIMSLGLL 17 370LLSLLAVTS 17 410 VLIYGWKRA 17 428 TPPNFVLAL 17 438 LPSIVILDL 17 442VILDLLQLC 17 25 IKDARKVTV 16 68 EFFPHVVDV 16 88 IIFVAIHRE 16 93IHREHYTSL 16 99 TSLWDLRHL 16 132 YLASLFPDS 16 148 VVSAWALQL 16 171NIQARQQVI 16 190 IDLGSLSSA 16 200 EIENLPLRL 16 372 SLLAVTSIP 16 12SLSETCLPN 15 44 SLTIRIIRC 15 50 IRCGYHVVI 15 111 KILIDVSNN 15 211LWRGPVVVA 15 217 VVAISLATF 15 221 SLATFFFLY 15 247 FYKIPIEIV 15 249KIPIEIVNK 15 251 PIEIVNKTL 15 256 NKTLPIVAI 15 270 VYLAGLLAA 15 299LQCRKQLGL 15 324 PMRRSERYL 15 331 YLFLNMAYQ 15 335 NMAYQQVHA 15 385ALNWREFSF 15 400 YVALLISTF 15 437 VLPSIVILD 15 23 NGIKDARKV 14 37GSGDFAKSL 14 39 GDFAKSLTI 14 42 AKSLTIRII 14 164 QVYICSNNI 14 166YICSNNIQA 14 220 ISLATFFFL 14 223 ATFFFLYSF 14 266 LLSLVYLAG 14 275LLAAAYQLY 14 278 AAYQLYYGT 14 300 QCRKQLGLL 14 309 SFFFAMVHV 14 362SFGIMSLGL 14 373 LLAVTSIPS 14 395 QSTLGYVAL 14 411 LIYGWKRAF 14 427YTPPNFVLA 14 443 ILDLLQLCR 14

TABLE XXIII V2-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 GLQALSLSL 25 1 SGSPGLQAL 21 8ALSLSLSSG 18 17 FTPFSCLSL 17 10 SLSLSSGFT 16 3 SPGLQALSL 15 12 SLSSGFTPF14 15 SGFTPFSGL 14 24 SLPSSWDYR 12

TABLE XXIII V5A-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 FTFWRGPVV 17 1 NLPLRLFTF 16 8TFWRGPVVV 15 9 FWRGPVVVA 14 5 RLFTFWRGP 13 3 PLRLFTFWR 10 6 LFTFWRGPV 10

TABLE XXIII V5B-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 20 LELEFVFLL 21 22 LEFVFLLTL 21 24FVFLLTLLL 20 19 ELELEFVFL 18 12 SFADTQTEL 17 17 QTELELEFV 17 8 QIFCSFADT15 6 FIQIFCSFA 14 14 ADTQTELEL 14 23 EFVFLLTLL 11 21 ELEFVFLLT 10

TABLE XXIII V6-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 ILGKIILFL 27 38 GIGGTIPHV 26 10KIILFLPCI 25 14 FLPCISRKL 23 34 FLEEGIGGT 23 5 IVILGKIIL 20 17 CISRKLKRI20 45 HVSPERVTV 20 4 SIVILGKII 18 6 VILGKIILF 18 12 ILFLPCISR 16 1VLPSIVILG 15 27 KGWEKSQFL 15 3 PSIVILGKI 13 35 LEEGIGGTI 13 41 GTIPHVSPE13

TABLE XXIII V7A-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 FLPNGINGI 27 4 SLSETFLPN 15

TABLE XXIII V7B-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 STLGYVALL 27 3 NMAYQQSTL 21 6YQQSTLGYV 16 8 QSTLGYVAL 14

TABLE XXIII V7C-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 27 ILRGGLSEI 30 4 VILDLSVEV 27 5ILDLSVEVL 26 31 GLSEIVLPI 26 129 PLWEFLLRL 26 148 SLAFTSWSL 25 2SIVILDLSV 24 141 QAASGTLSL 23 155 SLGEFLGSG 21 163 GTWMKLETI 21 81SSQIPVVGV 20 82 SQIPVVGVV 20 119 PVLPHTNGV 19 133 FLLRLLKSQ 19 165WMKLETIIL 19 24 GANILRGGL 18 57 AMWTEEAGA 18 112 AANSWRNPV 18 126GVGPLWEFL 18 12 VLASPAAAW 17 79 SSSSQPIVV 17 134 LLRLLKSQA 17 167KLETIILSK 17 168 LETIILSKL 17 171 IILSKLTQE 17 172 ILSKLTQEQ 17 42QQDRKIPPL 16 142 AASGTLSLA 16 160 LGSGTWMKL 16 7 DLSVEVLAS 15 17AAAWKCLGA 15 22 CLGANILRG 15 26 NILRGGLSE 15 28 LRGGLSEIV 15 130LWEFLLRLL 15 136 RLLKSQAAS 15 137 LLKSQAASG 15 159 FLGSGTWMK 15 185CMFSLISGS 15 83 QIPVVGVVT 14

TABLE XXIII V8-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 GMGGTIPHV 26 4 FLEEGMGGT 19 5LEEGMGGTI 13

TABLE XXIII V13-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 FLPNGINGI 27 4 SLSETFLPN 15

TABLE XXIII V14-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 FTFWRGPVV 17 1 NLPLRLFTF 16 8TFWRGPVVV 15 9 FWRGPVVVA 14 5 RLFTFWRGP 13 3 PLRLFTFWR 10 6 LFTFWRGPV 10

TABLE XXIII V21-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 KTKHCMFSL 16 2 KLTQEQKTK 11 1SKLTQEQKT 10 3 LTQEQKTKH 10 9 TKHCMFSLI 8

TABLE XXIII V25-HLA-A0201-9mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 FLPCISQKL 23 6 CISQKLKRI 20 1ILFLPCISQ 16

TABLE XXIV V1-HLA-A0203-9mers-98P4B6 Pos 123456789 score NoResultsFound.

TABLE XXIV V2-HLA-A0203-9mers-98P4B6 Pos 123456789 score NoResultsFound.

TABLE XXIV V5A-HLA-A0203-9mers-98P4B6 Pos 123456789 scoreNoResultsFound.

TABLE XXIV V5B-HLA-A0203-9mers-98P4B6 Pos 123456789 scoreNoResultsFound.

TABLE XXIV V6-HLA-A0203-9mers-98P4B6 Pos 123456789 score NoResultsFound.

TABLE XXIV V7A-HLA-A0203-9mers-98P4B6 Pos 123456789 scoreNoResultsFound.

TABLE XXIV V7B-HLA-A0203-9mers-98P4B6 Pos 123456789 scoreNoResultsFound.

TABLE XXIV V7C-HLA-A0203-9mers-98P4B6 Pos 123456789 scoreNoResultsFound.

TABLE XXIV V8-HLA-A0203-9mers-98P4B6 Pos 123456789 score NoResultsFound.

TABLE XXIV V13-HLA-A0203-9mers-98P4B6 Pos 123456789 scoreNoResultsFound.

TABLE XXIV V14-HLA-A0203-9mers-98P4B6 Pos 123456789 scoreNoResultsFound.

TABLE XXIV V21-HLA-A0203- 9mers-98P4B6 Pos 123456789 score No ResultsFound.

TABLE XXIV V25-HLA-A0203- 9mers-98P4B6 Pos 123456789 score No ResultsFound.

TABLE XXV V1-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 103 DLRHLLVGK 27 56 VVIGSRNPK 26 249KIPIEIVNK 26 3 SISMMGSPK 25 155 QLGPKDASR 25 263 AITLLSLVY 25 210TLWRGPVVV 24 48 RLIRCGYHV 23 142 IVKGFNVVS 23 217 VVAISLATF 23 400YVALLISTF 23 177 QVIELARQL 22 205 PLRLFTLWR 22 281 QLYYGTKYR 22 370LLSLLAVTS 22 441 IVILDLLQL 22 35 VIGSGDFAK 21 77 THHEDALTK 21 148VVSAWALQL 21 231 FVRDVIHPY 21 269 LVYLAGLLA 21 375 AVTSIPSVS 21 385ALNWREFSF 21 274 GLLAAAYQL 20 322 CLPMRRSER 20 409 HVLIYGWKR 20 443ILDLLQLCR 20 46 TIRLIRCGY 19 87 NIIFVAIHR 19 90 FVAIHREHY 19 258TLPIVAITL 19 261 IVAITLLSL 19 275 LLAAAYQLY 19 279 AYQLYYGTK 19 369GLLSLLAVT 19 372 SLLAVTSIP 19 411 LIYGWKRAF 19 436 LVLPSIVIL 19 34GVIGSGDFA 18 92 AIHREHYTS 18 140 SLIVKGFNV 18 191 DLGSLSSAR 18 221SLATFFFLY 18 435 ALVLPSIVI 18 22 INGIKDARK 17 49 LIRCGYHVV 17 82ALTKTNIIF 17 111 KILIDVSNN 17 112 ILIDVSNNM 17 135 SLFPDSLIV 17 153ALQLGPKDA 17 164 QVYICSNNI 17 203 NLPLRLFTL 17 271 YLAGLLAAA 17 304QLGLLSFFF 17 381 SVSNALNWR 17 397 TLGYVALLI 17 403 LLISTFHVL 17 432FVLALVLPS 17 32 TVGVIGSGD 16 107 LLVGKILID 16 151 AWALQLGPK 16 171NIQARQQVI 16 189 PIDLGSLSS 16 216 VVVAISLAT 16 219 AISLATFFF 16 234DVIHPYARN 16 266 LLSLVYLAG 16 302 RKQLGLLSF 16 402 ALLISTFHV 16 12SLSETCLPN 15 21 GINGIKDAR 15 24 GIKDARKVT 15 30 KVTVGVIGS 15 121RINQYPESN 15 136 LFPDSLIVK 15 179 IELARQLNF 15 268 SLVYLAGLL 15 356RIEMYISFG 15 367 SLGLLSLLA 15 410 VLIYGWKRA 15 433 VLALVLPSI 15 25IKDARKVTV 14 44 SLTIRLIRC 14 57 VIGSRNPKF 14 61 RNPKFASEF 14 106HLLVGKILI 14 141 LIVKGFNVV 14 180 ELARQLNFI 14

TABLE XXV V1-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 207 RLFTLWRGP 14 227 FLYSFVRDV 14 235VIHPYARNQ 14 241 RNQQSDFYK 14 251 PIEIVNKTL 14 272 LAGLLAAAY 14 294WLETWLQCR 14 303 KQLGLLSFF 14 307 LLSFFFAMV 14 330 RYLFLNMAY 14 331YLFLNMAYQ 14 340 QVHANIENS 14 353 EVWRIEMYI 14 364 GIMSLGLLS 14 17CLPNGINGI 13 18 LPNGINGIK 13 26 KDARKVTVG 13 43 KSLTIRLIR 13 55HVVIGSRNP 13 70 FPHVVDVTH 13 100 SLWDLRHLL 13 113 LIDVSNNMR 13 147NVVSAWALQ 13 158 PKDASRQVY 13 184 QLNFIPIDL 13 200 EIENLPLRL 13 211LWRGPVVVA 13 215 PVVVAISLA 13 253 EIVNKTLPI 13 260 PIVAITLLS 13 306GLLSFFFAM 13 311 FFAMVHVAY 13 314 MVHVAYSLC 13 333 FLNMAYQQV 13 360YISFGIMSL 13 392 SFIQSTLGY 13 408 FHVLIYGWK 13 440 SIVILDLLQ 13

TABLE XXV V2-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:5; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Pos 123456789 score 8 ALSLSLSSG 19 12 SLSSGFTPE 18 5 GLQALSLSL 1722 CLSLPSSWD 15 24 SLPSSWDYR 15 10 SLSLSSGFT 13 23 LSLPSSWDY 11 33CPPPCPADF 11 3 SPGLQALSL 10 7 QALSLSLSS 9 9 LSLSLSSGF 9 11 LSLSSGFTP 921 SCLSLPSSW 9 37 CPADFFLYF 9

TABLE XXV V5A-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 21 3 PLRLFTFWR 19 5RLFTFWRGP 14 8 TFWRGPVVV 14 9 FWRGPVVVA 13

TABLE XXV V5B-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 19 ELELEFVFL 15 21 ELEFVFLLT 14 24FVFLLTLLL 14 8 QIFCSFADT 13 6 FIQIFCSFA 12 18 TELELEFVF 11 5 SFIQIFCSF10 9 IFCSFADTQ 9 2 REFSFIQIF 8 16 TQTELELEF 8 22 LEFVFLLTL 7

TABLE XXV V6-HLA-A3-9mers-98P4B6 Each peptide is a portion of SEQ ID NO:13; each start position is specified, the length of peptide is 9 aminoacids, and the end position for each peptide is the start position pluseight. Pos 123456789 score 45 HVSPERVTV 22 23 KRIKKGWEK 20 12 ILFLPCISR19 5 IVILGKIIL 18 13 LFLPCISRK 18 6 VILGKIILF 17 21 KLKRIKKGW 17 2LPSIVILGK 15 7 ILGKIILFL 15 10 KIILFLPCI 15 18 ISRKLKRIK 15 19 SRKLKRIKK15 24 RIKKGWEKS 15 34 FLEEGIGGT 14 4 SIVILGKII 13 11 IILFLPCIS 13 26KKGWEKSQF 13 42 TIPHVSPER 13 15 LPCISRKLK 12 16 PCISRKLKR 12 17CISRKLKRI 12 37 EGIGGTIPH 11 1 VLPSIVILG 10 14 FLPCISRKL 10 35 LEEGIGGTI10 38 GIGGTIPHV 10

TABLE XXV V7A-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 SLSETFLPN 15 9 FLPNGINGI 13 1SPKSLSETF 10 8 TFLPNGING 8

TABLE XXV V7B-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 FLNMAYQQS 13 5 AYQQSTLGY 12 8QSTLGYVAL 10 7 QQSTLGYVA 9 3 NMAYQQSTL 8 9 STLGYVALL 8 4 MAYQQSTLG

TABLE XXV V7C-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 167 KLETIILSK 28 175 KLTQEQKSK 25 109ALKAANSWR 24 3 IVILDLSVE 23 26 NILRGGLSE 23 159 FLGSGTWMK 23 27ILRGGLSEI 22 83 QIPVVGVVT 22 13 LASPAAAWK 20 35 IVLPIEWQQ 20 134LLRLLKSQA 20 136 RLLKSQAAS 20 11 EVLASPAAA 19 137 LLKSQAASG 19 170TIILSKLTQ 19 12 VLASPAAAW 18 38 PIEWQQDRK 18 73 GIRNKSSSS 18 5 ILDLSVEVL17 9 SVEVLASPA 17 45 RKIPPLSTP 17 103 PESPDRALK 17 133 FLLRLLKSQ 17 171IILSKLTQE 17 2 SIVILDLSV 15 4 VILDLSVEV 15 22 CLGANILRG 15 46 KIPPLSTPP15 69 AQESGIRNK 15 99 SIDPPESPD 15 119 PVLPHTNGV 15 120 VLPHTNGVG 15 131WEFLLRLLK 15 155 SLGEFLGSG 15 173 LSKLTQEQK 15 7 DLSVEVLAS 14 31GLSEIVLPI 14 36 VLPIEWQQD 14 85 PVVGVVTED 14 129 PLWEFLLRL 14 146TLSLAFTSW 14 148 SLAFTSWSL 14 25 ANILRGGLS 13 82 SQIPVVGVV 13 126GVGPLWEFL 13

TABLE XXV V8-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 FLEEGMGGT 14 5 LEEGMGGTI 10 3QFLEEGMGG 9 7 EGMGGTIPH 8 6 EEGMGGTIP 6

TABLE XXV V13-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 SLSETFLPN 15 9 FLPNGINGI 13 1SPKSLSETF 10 8 TFLPNGING 8

TABLE XXV V14-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 21 3 PLRLFTFWR 19 5RLFTFWRGP 14 8 TFWRGPVVV 14 9 FWRGPVVVA 13

TABLE XXV V21-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 KLTQEQKTK 27

TABLE XXV V25-HLA-A3- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 LFLPCISQK 21 1 ILFLPCISQ 15 8SQKLKRIKK 15 7 ISQKLKRIK 12 4 LPCISQKLK 11 3 FLPCISQKL 10 5 PCISQKLKR 10

TABLE XXVI V1-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 352 EEVWRIEMY 29 75 DVTHHEDAL 28 441IVILDLLQL 28 177 QVIELARQL 26 223 ATFFFLYSF 25 231 FVRDVIHPY 25 400YVALLISTF 25 200 EIENLPLRL 24 261 IVAITLLSL 24 217 VVAISLATF 23 436LVLPSIVIL 23 96 EHYTSLWDL 22 234 DVIHPYARN 22 353 EVWRIEMYI 22 390EFSFIQSTL 22 396 STLGYVALL 21 90 FVAIHREHY 20 148 VVSAWALQL 20 253EIVNKTLPI 20 264 ITLLSLVYL 20 15 ETCLPNGIN 19 68 EFFPHVVDV 19 115DVSNNMRIN 19 215 PVVVAISLA 19 296 ETWLQCRKQ 19 31 VTVGVIGSG 18 187FIPIDLGSL 18 216 VVVAISLAT 18 406 STFHVLIYG 18 439 PSIVILDLL 18 2ESISMMGSP 17 45 LTIRLIRCG 17 46 TIRLIRCGY 17 108 LVGKILIDV 17 263AITLLSLVY 17 360 YISFGIMSL 17 363 FGIMSLGLL 17 30 KVTVGVIGS 16 117SNNMRINQY 16 128 SNAEYLASL 16 259 LPIVAITLL 16 355 WRIEMYISF 16 392SFIQSTLGY 16 405 ISTFHVLIY 16 432 FVLALVLPS 16 32 TVGVIGSGD 15 34GVIGSGDFA 15 72 HVVDVTHHE 15 147 NVVSAWALQ 15 257 KTLPIVAIT 15 268SLVYLAGLL 15 329 ERYLFLNMA 15 340 QVHANIENS 15 375 AVTSIPSVS 15 378SIPSVSNAL 15 381 SVSNALNWR 15 428 TPPNFVLAL 15 55 HVVIGSRNP 14 56VVIGSRNPK 14 57 VIGSRNPKF 14 83 LTKTNIIFV 14 131 EYLASLFPD 14 138PDSLIVKGF 14 180 ELARQLNFI 14 214 GPVVVAISL 14 218 VAISLATFF 14 254IVNKTLPIV 14 302 RKQLGLLSF 14 303 KQLGLLSFF 14 316 HVAYSLCLP 14 365IMSLGLLSL 14 366 MSLGLLSLL 14 430 PNFVLALVL 14 444 LDLLQLCRY 14

TABLE XXVI V2-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 17 FTPFSCLSL 18 1 SGSPGLQAL 15 15SGFTPFSCL 14 3 SPGLQALSL 11 5 GLQALSLSL 11 9 LSLSLSSGF 11 18 TPFSCLSLP11 23 LSLPSSWDY 11 12 SLSSGFTPF 10 36 PCPADFFLY 10 37 CPADFFLYF 10 33CPPPCPADF 9 35 PPCPADFFL 9 30 DYRCPPPCP 8 34 PPPCPADFF 8

TABLE XXVI V5A-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 13 7 FTFWRGPVV 13

TABLE XXVI V5B-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 23 EFVFLLTLL 27 24 FVFLLTLLL 24 15DTQTELELE 20 19 ELELEFVFL 18 22 LEFVFLLTL 18 2 REFSFIQIF 17 5 SFIQIFCSF16 16 TQTELELEF 14 20 LELEFVFLL 14 3 EFSFIQIFC 13

TABLE XXVI V6-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 IVILGKIIL 23 6 VILGKIILF 18 41GTIPHVSPE 18 7 ILGKIILFL 15 37 EGIGGTIPH 15 30 EKSQFLEEG 14 3 PSIVILGKI12 10 KIILFLPCI 12 45 HVSPERVTV 12 4 SIVILGKII 11 14 FLPCISRKL 11 27KGWEKSQFL 11 36 EEGIGGTIP 11

TABLE XXVI V7A-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 ETFLPNGIN 23 1 SPKSLSETF 12

TABLE XXVI V7B-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 STLGYVALL 21 5 AYQQSTLGY 11 3NMAYQQSTL 10 8 QSTLGYVAL 10

TABLE XXVI V7C-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 169 ETIILSKLT 23 34 EIVLPIEWQ 22 11EVLASPAAA 21 151 FTSWSLGEF 21 179 EQKSKHCMF 21 126 GVGPLWEFL 20 3IVILDLSVE 19 85 PVVGVVTED 18 168 LETIILSKL 17 125 NGVGPLWEF 16 132EFLLRLLKS 16 95 EAQDSIDPP 15 129 PLWEFLLRL 15 7 DLSVEVLAS 14 35IVLPIEWQQ 14 68 EAQESGIRN 14 88 GVVTEDDEA 14 89 VVTEDDEAQ 14 98DSIDPPESP 14 122 PHTNGVGPL 14 163 GTWMKLETI 14 9 SVEVLASPA 13 42QQDRKIPPL 13 92 EDDEAQDSI 13 104 ESPDRALKA 13 130 LWEFLLRLL 13 2SIVILDLSV 12 5 ILDLSVEVL 12 59 WTEEAGATA 12 152 TSWSLGEFL 12 176LTQEQKSKH 12 8 LSVEVLASP 11 45 RKIPPLSTP 11 51 STPPPPAMW 11 62 EAGATAEAQ11 65 ATAEAQESG 11 71 ESGIRNKSS 11 82 SQIPVVGVV 11 119 PVLPHTNGV 11 141QAASGTLSL 11 143 ASGTLSLAF 11 145 GTLSLAFTS 11 158 EFLGSGTWM 11 170TIILSKLTQ 11 171 IILSKLTQE 11 185 CMFSLISGS 11

TABLE XXVI V8-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 6 EEGMGGTIP 11 7 EGMGGTIPH 11 2SQFLEEGMG 7

TABLE XXVI V13-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 ETFLPNGIN 23 1 SPKSLSETF 12

TABLE XXVI V14-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 13 7 FTFWRGPVV 13

TABLE XXVI V21-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 6 EQKTKHCMF 20 8 KTKHCMFSL 17 3LTQEQKTKH 11

TABLE XXVI V25-HLA-A26- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 FLPCISQKL 11 6 CISQKLKRI 9 2 LFLPCISQK7 5 PCISQKLKR 7 1 ILFLPCISQ 6 9 QKLKRIKKG 5

TABLE XXVII V1-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 428 TPPNFVLAL 24 438 LPSIVILDL 24 259LPIVAITLL 21 291 FPPWLETWL 21 125 YPESNAEYL 20 214 GPVVVAISL 20 250IPIEIVNKT 18 62 NPKFASEFF 17 211 LWRGPVVVA 17 429 PPNFVLALV 17 157GPKDASRQV 16 326 RRSERYLFL 16 148 VVSAWALQL 15 198 AREIENLPL 15 365IMSLGLLSL 15 426 FYTPPNFVL 15 93 IHREHYTSL 14 220 ISLATFFFL 14 261IVAITLLSL 14 287 KYRRFPPWL 14 379 IPSVSNALN 14 396 STLGYVALL 14 5SMMGSPKSL 13 10 PKSLSETCL 13 137 FPDSLIVKG 13 173 QARQQVIEL 13 200EIENLPLRL 13 264 ITLLSLVYL 13 289 RRFPPWLET 13 300 QCRKQLGLL 13 315VHVAYSLCL 13 362 SFGIMSLGL 13 390 EFSFIQSTL 13 395 QSTLGYVAL 13 430PNFVLALVL 13 436 LVLPSIVIL 13 441 IVILDLLQL 13 18 LPNGINGIK 12 27DARKVTVGV 12 50 IRCGYHVVI 12 70 FPHVVDVTH 12 105 RHLLVGKIL 12 128SNAEYLASL 12 133 LASLFPDSL 12 188 IPIDLGSLS 12 202 ENLPLRLFT 12 204LPLRLFTLW 12 212 WRGPVVVAI 12 219 AISLATFFF 12 256 NKTLPIVAI 12 299LQCRKQLGL 12 313 AMVHVAYSL 12 324 PMRRSERYL 12 360 YISFGIMSL 12 366MSLGLLSLL 12 403 LLISTFHVL 12 435 ALVLPSIVI 12 25 IKDARKVTV 11 37GSGDFAKSL 11 41 FAKSLTIRL 11 68 EFFPHVVDV 11 75 DVTHHEDAL 11 85KTNIIFVAI 11 96 EHYTSLWDL 11 100 SLWDLRHLL 11 134 ASLFPDSLI 11 146FNVVSAWAL 11 196 SSAREIENL 11 237 HPYARNQQS 11 253 EIVNKTLPI 11 267LSLVYLAGL 11 271 YLAGLLAAA 11 274 GLLAAAYQL 11 292 PPWLETWLQ 11 297TWLQCRKQL 11 323 LPMRRSERY 11 328 SERYLFLNM 11 378 SIPSVSNAL 11 394IQSTLGYVA 11 425 RFYTPPNFV 11

TABLE XXVII V2-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 SPGLQALSL 23 35 PPCPADFFL 22 34PPPCPADFF 20 37 CPADFFLYF 20 33 CPPPCPADF 18 1 SGSPGLQAL 14 15 SGFTPFSCL14 5 GLQALSLSL 13 17 FTPFSCLSL 12 25 LPSSWDYRC 12 12 SLSSGFTPF 11 31YRCPPPCPA 11

TABLE XXVII V5A-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 FWRGPVVVA 17 2 LPLRLFTFW 13 7FTFWRGPVV 9 8 TFWRGPVVV 9 6 LFTFWRGPV 8

TABLE XXVII V5B-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 19 ELELEFVFL 15 14 ADTQTELEL 14 24FVFLLTLLL 13 12 SFADTQTEL 12 22 LEFVFLLTL 12 23 EFVFLLTLL 12 20LELEFVFLL 11 21 ELEFVFLLT 10 10 FCSFADTQT 9 8 QIFCSFADT 8 16 TQTELELEF 81 WREFSFIQI 7 2 REFSFIQIF 7 5 SFIQIFCSF 7 6 FIQIFCSFA 7 17 QTELELEFV 718 TELELEFVF 7

TABLE XXVII V6-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 43 IPHVSPERV 17 7 ILGKIILFL 16 2LPSIVILGK 14 27 KGWEKSQFL 12 45 HVSPERVTV 12 5 IVILGKIIL 11 15 LPCISRKLK11 14 FLPCISRKL 10 38 GIGGTIPHV 10 44 PHVSPERVT 10 35 LEEGIGGTI 9 46VSPERVTVM 9 6 VILGKIILF 8 10 KIILFLPCI 8 17 CISRKLKRI 8 26 KKGWEKSQF 8

TABLE XXVII V7A-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 SPKSLSETF 16 2 PKSLSETFL 14

TABLE XXVII V7B-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 STLGYVALL 14 8 QSTLGYVAL 13 3NMAYQQSTL 11 7 QQSTLGYVA 10 2 LNMAYQQST 8 6 YQQSTLGYV 6

TABLE XXVII V7C-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 102 PPESPDRAL 24 15 SPAAAWKCL 22 52TPPPPAMWT 20 55 PPAMWTEEA 18 105 SPDRALKAA 18 101 DPPESPDRA 16 113ANSWRNPVL 16 5 ILDLSVEVL 14 47 IPPLSTPPP 14 84 IPVVGVVTE 14 118NPVLPHTNG 14 141 QAASGTLSL 14 160 LGSGTWMKL 14 29 RGGLSEIVL 13 42QQDRKIPPL 13 49 PLSTPPPPA 13 121 LPHTNGVGP 13 126 GVGPLWEFL 13 128GPLWEFLLR 13 31 GLSEIVLPI 12 48 PPLSTPPPP 12 50 LSTPPPPAM 12 54PPPAMWTEE 12 61 EEAGATAEA 12 81 SSQIPVVGV 12 122 PHTNGVGPL 12 129PLWEFLLRL 12 139 KSQAASGTL 12 142 AASGTLSLA 12 143 ASGTLSLAF 12 152TSWSLGEFL 12 17 AAAWKCLGA 11 24 GANILRGGL 11 27 ILRGGLSEI 11 44DRKIPPLST 11 53 PPPPAMWTE 11 125 NGVGPLWEF 11 148 SLAFTSWSL 11 158EFLGSGTWM 11 165 WMKLETIIL 11 181 KSKHCMFSL 11

TABLE XXVII V8-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 GMGGTIPHV 10 5 LEEGMGGTI 9 1 KSQFLEEGM7 4 FLEEGMGGT 6 7 EGMGGTIPH 6 6 EEGMGGTIP 4

TABLE XXVII V13-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 SPKSLSETF 16 2 PKSLSETFL 14

TABLE XXVII V14-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 FWRGPVVVA 17 2 LPLRLFTFW 13 7FTFWRGPVV 9 8 TFWRGPVVV 9 6 LFTFWRGPV 8

TABLE XXVII V21-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 KTKHCMFSL 11 5 QEQKTKHCM 7 6 EQKTKHCMF7 9 TKHCMFSLI 7 1 SKLTQEQKT 6

TABLE XXVII V25-HLA-B0702- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 FLPCISQKL 10 4 LPCISQKLK 10 6CISQKLKRI 8 1 ILFLPCISQ 4

TABLE XXVIII V1-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 41 FAKSLTIRL 25 203 NLPLRLFTL 25 62NPKFASEFF 22 173 QARQQVIEL 22 253 EIVNKTLPI 22 57 VIGSRNPKF 20 81DALTKTNII 20 285 GTKYRRFPP 20 299 LQCRKQLGL 20 326 RRSERYLFL 20 385ALNWREFSF 20 93 IHREHYTSL 19 140 SLIVKGFNV 19 268 SLVYLAGLL 19 9SPKSLSETC 18 28 ARKVTVGVI 18 100 SLWDLRHLL 18 171 NIQARQQVI 18 214GPVVVAISL 18 259 LPIVAITLL 18 428 TPPNFVLAL 18 39 GDFAKSLTI 17 107LLVGKILID 17 157 GPKDASRQV 17 274 GLLAAAYQL 17 291 FPPWLETWL 17 378SIPSVSNAL 17 438 LPSIVILDL 17 24 GIKDARKVT 16 44 SLTIRLIRC 16 125YPESNAEYL 16 155 QLGPKDASR 16 184 QLNFIPIDL 16 200 EIENLPLRL 16 237HPYARNQQS 16 239 YARNQQSDF 16 251 PIEIVNKTL 16 258 TLPIVAITL 16 283YYGTKYRRF 16 287 KYRRFPPWL 16 300 QCRKQLGLL 16 324 PMRRSERYL 16 403LLISTFHVL 16 133 LASLFPDSL 15 159 KDASRQVYI 15 179 IELARQLNF 15 187FIPIDLGSL 15 322 CLPMRRSER 15 360 YISFGIMSL 15 106 HLLVGKILI 14 128SNAEYLASL 14 180 ELARQLNFI 14 197 SAREIENLP 14 245 SDFYKIPIE 14 298WLQCRKQLG 14 323 LPMRRSERY 14 433 VLALVLPSI 14 5 SMMGSPKSL 13 17CLPNGINGI 13 82 ALTKTNIIF 13 91 VAIHREHYT 13 103 DLRHLLVGK 13 142IVKGFNVVS 13 146 FNVVSAWAL 13 196 SSAREIENL 13 205 PLRLFTLWR 13 264ITLLSLVYL 13 304 QLGLLSFFF 13 395 QSTLGYVAL 13 396 STLGYVALL 13 397TLGYVALLI 13 435 ALVLPSIVI 13 37 GSGDFAKSL 12 60 SRNPKFASE 12 96EHYTSLWDL 12 105 RHLLVGKIL 12 109 VGKILIDVS 12 177 QVIELARQL 12 247FYKIPIEIY 12 325 MRRSERYLF 12 362 SFGIMSLGL 12 365 IMSLGLLSL 12 390EFSFIQSTL 12 414 GWKRAFEEE 12 426 FYTPPNFVL 12 436 LVLPSIVIL 12 441IVILDLLQL 12

TABLE XXVIII V2-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 SPGLQALSL 19 5 GLQALSLSL 17 35PPCPADFFL 16 12 SLSSGFTPF 14 1 SGSPGLQAL 13 15 SGFTPFSCL 12 33 CPPPCPADF12 34 PPPCPADFF 12 37 CPADFFLYF 12 17 FTPFSCLSL 11 28 SWDYRCPPP 11 10SLSLSSGFT 9

TABLE XXIX V5A-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 21 3 PLRLFTFWR 13

TABLE XXIX V5B-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 19 ELELEFVFL 20 12 SFADTQTEL 13 20LELEFVFLL 13 23 EFVFLLTLL 12 24 FVFLLTLLL 12 14 ADTQTELEL 11 22LEFVFLLTL 11 16 TQTELELEF 9

TABLE XXIX V6-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 19 SRKLKRIKK 23 6 VILGKIILF 22 27KGWEKSQFL 22 17 CISRKLKRI 21 7 ILGKIILFL 18 14 FLPCISRKL 17 21 KLKRIKKGW17 22 LKRIKKGWE 16 24 RIKKGWEKS 14 4 SIVILGKII 13 5 IVILGKIIL 12 25IKKGWEKSQ 12 46 VSPERVTVM 12 10 KIILFLPCI 11 23 KRIKKGWEK 11 29WEKSQFLEE 11

TABLE XXIX V7A-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 SPKSLSETF 24 9 FLPNGINGI 14 2PKSLSETFL 11

TABLE XXIX V7B-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 QSTLGYVAL 13 9 STLGYVALL 13 3NMAYQQSTL 11 1 FLNMAYQQS 7

TABLE XXIX V7C-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 179 EQKSKHCMF 28 42 QQDRKIPPL 21 73GIRNKSSSS 21 165 WMKLETIIL 21 27 ILRGGLSEI 20 181 KSKHCMFSL 20 5ILDLSVEVL 19 15 SPAAAWKCL 19 113 ANSWRNPVL 19 129 PLWEFLLRL 18 148SLAFTSWSL 18 102 PPESPDRAL 17 109 ALKAANSWR 17 163 GTWMKLETI 17 19AWKCLGANI 16 31 GLSEIVLPI 16 137 LLKSQAASG 16 24 GANILRGGL 15 171IILSKLTQE 15 17 AAAWKCLGA 14 141 QAASGTLSL 14 134 LLRLLKSQA 13

TABLE XXIX V8-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 FLEEGMGGT 9 5 LEEGMGGTI 6

TABLE XXIX V13-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 SPKSLSETF 24 9 FLPNGINGI 14 2PKSLSETFL 11

TABLE XXIX V14-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 21 3 PLRLFTFWR 13

TABLE XXIX V21-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 6 EQKTKHCMF 28 8 KTKHCMFSL 20 4TQEQKTKHC 11

TABLE XXIX V25-HLA-B08- 9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 SQKLKRIKK 23 6 CISQKLKRI 21 3FLPCISQKL 17

TABLE XXIX V1-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 93 IHREHYTSL 23 96 EHYTSLWDL 21 105RHLLVGKIL 20 315 VHVAYSLCL 20 200 EIENLPLRL 15 426 FYTPPNFVL 15 436LVLPSIVIL 15 54 YHVVIGSRN 14 264 ITLLSLVYL 14 360 YISFGIMSL 14 365IMSLGLLSL 14 395 QSTLGYVAL 14 77 THHEDALTK 13 99 TSLWDLRHL 13 125YPESNAEYL 13 173 QARQQVIEL 13 177 QVIELARQL 13 236 IHPYARNQQ 13 261IVAITLLSL 13 297 TWLQCRKQL 13 390 EFSFIQSTL 13 428 TPPNFVLAL 13 430PNFVLALVL 13 5 SMMGSPKSL 12 37 GSGDFAKSL 12 41 FAKSLTIRL 12 71 PHVVDVTHH12 78 HHEDALTKT 12 100 SLWDLRHLL 12 128 SNAEYLASL 12 133 LASLFPDSL 12146 FNVVSAWAL 12 196 SSAREIENL 12 214 GPVVVAISL 12 220 ISLATFFFL 12 251PIEIVNKTL 12 258 TLPIVAITL 12 259 LPIVAITLL 12 287 KYRRFPPWL 12 324PMRRSERYL 12 326 RRSERYLFL 12 396 STLGYVALL 12 403 LLISTFHVL 12 438LPSIVILDL 12 441 IVILDLLQL 12 10 PKSLSETCL 11 75 DVTHHEDAL 11 148VVSAWALQL 11 184 QLNFIPIDL 11 198 AREIENLPL 11 201 IENLPLRLF 11 203NLPLRLFTL 11 267 LSLVYLAGL 11 274 GLLAAAYQL 11 283 YYGTKYRRF 11 300QCRKQLGLL 11 341 VHANIENSW 11 351 EEEVWRIEM 11 366 MSLGLLSLL 11 378SIPSVSNAL 11 383 SNALNWREF 11 411 LIYGWKRAF 11 439 PSIVILDLL 11

TABLE XXIX V2-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 SGSPGLQAL 15 35 PPCPADFFL 12 5GLQALSLSL 11 15 SGFTPFSCL 11 3 SPGLQALSL 10 17 FTPFSCLSL 10 33 CPPPCPADF9 12 SLSSGFTPF 8 37 CPADFFLYF 8 34 PPPCPADFF 7

TABLE XXIX V5A-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 7 8 TFWRGPVVV 7 9 FWRGPVVVA7 7 FTFWRGPVV 3

TABLE XXIX V5B-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 19 ELELEFVFL 14 12 SFADTQTEL 13 14ADTQTELEL 12 20 LELEFVFLL 12 22 LEFVFLLTL 12 23 EFVFLLTLL 11 18TELELEFVF 10 24 FVFLLTLLL 10 16 TQTELELEF 9 2 REFSFIQIF 7 5 SFIQIFCSF 7

TABLE XXIX V6-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 44 PHVSPERVT 15 5 IVILGKIIL 14 7ILGKIILFL 14 14 FLPCISRKL 12 27 KGWEKSQFL 11 46 VSPERVTVM 10 6 VILGKIILF8 26 KKGWEKSQF 7 45 HVSPERVTV 7

TABLE XXIX V7A-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 PKSLSETFL 11 1 SPKSLSETF 7

TABLE XXIX V7B-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 QSTLGYVAL 14 3 NMAYQQSTL 12 9STLGYVALL 12

TABLE XXIX V7C-HLA-B1510- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 122 PHTNGVGPL 22 5 ILDLSVEVL 15 102PPESPDRAL 15 113 ANSWRNPVL 14 126 GVGPLWEFL 13 129 PLWEFLLRL 13 130LWEFLLRLL 13 24 GANILRGGL 12 29 RGGLSEIVL 12 42 QQDRKIPPL 12 50LSTPPPPAM 12 141 QAASGTLSL 12 160 LGSGTWMKL 12 15 SPAAAWKCL 11 20WKCLGANIL 11 139 KSQAASGTL 11 148 SLAFTSWSL 11 152 TSWSLGEFL 11 181KSKHCMFSL 11 127 VGPLWEFLL 10 165 WMKLETIIL 10 168 LETIILSKL 10 183KHCMFSLIS 10

TABLE XXIX V8-HLA-B1510-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 KSQFLEEGM 6 4 FLEEGMGGT 4 8 GMGGTIPHV4 5 LEEGMGGTI 3 7 EGMGGTIPH 3 9 MGGTIPHVS 3 6 EEGMGGTIP 2

TABLE XXIX V13-HLA-B1510-9mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 PKSLSETFL 11 1 SPKSLSETF  7

TABLE XXIX V14-HLA-B1510-9mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 7 8 TFWRGPVVV 7 9 FWRGPVVVA7 7 FTFWRGPVV 3

TABLE XXIX V21-HLA-B1510-9mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 KTKHCMFSL 11  5 QEQKTKHCM 8 6EQKTKHCMF 7 4 TQEQKTKHC

TABLE XXIX V25-HLA-B1510-9mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 FLPCISQKL 10  7 ISQKLKRIK 6 6CISQKLKRI 4

TABLE XXIX V1-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 326 RRSERYLFL 26 424 YRFYTPPNF 26 355WRIEMYISF 25 198 AREIENLPL 24 240 ARNQQSDFY 22 325 MRRSERYLF 22 47IRLIRCGYH 21 50 IRCGYHVVI 21 104 LRHLLVGKI 21 289 RRFPPWLET 21 416KRAFEEEYY 21 212 WRGPVVVAI 20 302 RKQLGLLSF 20 417 RAFEEEYYR 20 28ARKVTVGVI 19 61 RNPKFASEF 19 182 ARQLNFIPI 19 199 REIENLPLR 19 249KIPIEIVNK 19 303 KQLGLLSFF 19 53 GYHVVIGSR 18 105 RHLLVGKIL 18 179IELARQLNF 18 214 GPVVVAISL 18 241 RNQQSDFYK 18 274 GLLAAAYQL 18 282LYYGTKYRR 18 436 LVLPSIVIL 18 21 GINGIKDAR 17 174 ARQQVIELA 17 223ATFFFLYSF 17 259 LPIVAITLL 17 264 ITLLSLVYL 17 330 RYLFLNMAY 17 360YISFGIMSL 17 365 IMSLGLLSL 17 366 MSLGLLSLL 17 400 YVALLISTF 17 430PNFVLALVL 17 441 IVILDLLQL 17 22 INGIKDARK 16 39 GDFAKSLTI 16 40DFAKSLTIR 16 43 KSLTIRLIR 16 56 VVIGSRNPK 16 112 ILIDVSNNM 16 175RQQVIELAR 16 177 QVIELARQL 16 196 SSAREIENL 16 206 LRLFTLWRG 16 218VAISLATFE 16 225 FFFLYSFVR 16 233 RDVIHPYAR 16 313 AMVHVAYSL 16 319YSLCLPMRR 16 396 STLGYVALL 16 418 AFEEEYYRF 16 443 ILDLLQLCR 16 37GSGDFAKSL 15 82 ALTKTNIIF 15 87 NIIFVAIHR 15 93 IHREHYTSL 15 96EHYTSLWDL 15 155 QLGPKDASR 15 173 QARQQVIEL 15 295 LETWLQCRK 15 297TWLQCRKQL 15 329 ERYLFLNMA 15 390 EFSFIQSTL 15 401 VALLISTFH 15 409HVLIYGWKR 15 411 LIYGWKRAF 15 438 LPSIVILDL 15 5 SMMGSPKSL 14 10PKSLSETCL 14 18 LPNGINGIK 14 33 VGVIGSGDF 14 41 FAKSLTIRL 14 57VIGSRNPKF 14 60 SRNPKFASE 14 77 THHEDALTK 14 120 MRINQYPES 14 128SNAEYLASL 14 136 LFPDSLIVK 14 146 FNVVSAWAL 14 162 SRQVYICSN 14 167ICSNNIQAR 14 193 GSLSSAREI 14 200 EIENLPLRL 14 201 IENLPLRLF 14 217VVAISLATF 14 258 TLPIVAITL 14 261 IVAITLLSL 14 263 AITLLSLVY 14 267LSLVYLAGL 14 280 YQLYYGTKY 14 281 QLYYGTKYR 14 299 LQCRKQLGL 14 301CRKQLGLLS 14 308 LSFFFAMVH 14 318 AYSLCLPMR 14 363 FGIMSLGLL 14 392SFIQSTLGY 14 395 QSTLGYVAL 14 426 FYTPPNFVL 14 439 PSIVILDLL 14 444LDLLQLCRY 14 35 VIGSGDFAK 13 98 YTSLWDLRH 13 99 TSLWDLRHL 13 103DLRIILLVGK 13 113 LIDVSNNMR 13 117 SNNMRINQY 13 124 QYPESNAEY 13 129NAEYLASLF 13 138 PDSLIVKGF 13 148 VVSAWALQL 13 151 AWALQLGPK 13 191DLGSLSSAR 13 203 NLPLRLFTL 13 220 ISLATFFFL 13 229 YSFVRDVIH 13 239YARNQQSDF 13 246 DFYKIPIEI 13 251 PIEIVNKTL 13 268 SLVYLAGLL 13 279AYQLYYGTK 13 283 YYGTKYRRF 13 287 KYRRFPPWL 13 291 FPPWLETWL 13 300QCRKQLGLL 13 304 QLGLLSFFF 13 306 GLLSFFFAM 13 315 VHVAYSLCL 13 337AYQQVHANI 13 348 SWNEEEVWR 13 371 LSLLAVTSI 13 378 SIPSVSNAL 13 388WREFSFIQS 13 403 LLISTFHVL 13 408 FHVLIYGWK 13 435 ALVLPSIVI 13 17CLPNGINGI 12 70 FPHVVDVTH 12 71 PHVVDVTHH 12 80 EDALTKTNI 12 86TNIIFVAIH 12 89 IFVAIHREH 12 106 HLLVGKILI 12 114 IDVSNNMRI 12 133LASLFPDSL 12 134 ASLFPDSLI 12 164 QVYICSNNI 12 184 QLNFIPIDL 12 187FIPIDLGSL 12 205 PLRLFTLWR 12 219 AISLATFFF 12 231 FVRDVIHPY 12 232VRDVIHPYA 12 256 NKTLPIVAI 12 272 LAGLLAAAY 12 288 YRRFPPWLE 12 317VAYSLCLPM 12 322 CLPMRRSER 12 328 SERYLFLNM 12 349 WNEEEVWRI 12 352EEVWRIEMY 12 362 SFGIMSLGL 12 381 SVSNALNWR 12 383 SNALNWREF 12 385ALNWREFSF 12 428 TPPNFVLAL 12

TABLE XXX V2-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 GLQALSLSL 17 9 LSLSLSSGF 15 15SGFTPFSCL 15 1 SGSPGLQAL 14 3 SPGLQALSL 14 12 SLSSGFTPF 14 23 LSLPSSWDY14 17 FTPFSCLSL 13 31 YRCPPPCPA 12 33 GPPPCPADF 12 34 PPPCPADFF 12 35PPCPADFFL 12 24 SLPSSWDYR 11 37 CPADFFLYF 11 2 GSPGLQALS  9 36 PCPADFFLY 8

TABLE XXX V5A-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 LRLFTFWRG 15 1 NLPLRLFTF 13 3PLRLFTFWR 11 5 RLFTFWRGP  7

TABLE XXX V5B-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score  2 REFSFIQIF 20  1 WREFSFIQI 19  5SFIQIFCSF 16 22 LEFVFLLTL 16 24 FVFLLTLLL 16 12 SFADTQTEL 15 14ADTQTELEL 15 18 TELELEFVF 15 23 EFVFLLTLL 15 16 TQTELELEF 14 20LELEFVFLL 14 19 ELELEFVFL 13

TABLE XXX V6-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 23 KRIKKGWEK 29 19 SRKLKRIKK 25 6VILGKIILF 19 13 LFLPCISRK 19 5 IVILGKIIL 18 7 ILGKIILFL 18 12 ILFLPCISR18 16 PCISRKLKR 16 26 KKGWEKSQF 16 2 LPSIVILGK 15 18 ISRKLKRIK 15 27KGWEKSQFL 15 37 EGIGGTIPH 15 14 FLPCISRKL 14 42 TIPHVSPER 14

TABLE XXX V7A-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 PKSLSETFL 14 1 SPKSLSETF 13 9FLPNGINGI 12 6 SETFLPNGI  8 7 ETFLPNGIN  6 8 TFLPNGING  6

TABLE XXX V7B-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 STLGYVALL 16 3 NMAYQQSTL 14 8QSTLGYVAL 14 5 AYQQSTLGY 13 4 MAYQQSTLG  7

TABLE XXX V7C-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 21 KCLGANILR 18 29 RGGLSEIVL 18 69AQESGIRNK 18 167 KLETIILSK 18 175 KLTQEQKSK 18 74 IRNKSSSSS 17 125NGVGPLWEF 17 128 GPLWEFLLR 17 107 DRALKAANS 16 131 WEFLLRLLK 16 5ILDLSVEVL 15 20 WKCLGANIL 15 37 LPIEWQQDR 15 42 QQDRKIPPL 15 67AEAQESGIR 15 100 IDPPESPDR 15 126 GVGPLWEFL 15 129 PLWEFLLRL 15 135LRLLKSQAA 15 158 EFLGSGTWM 15 160 LGSGTWMKL 15 168 LETIILSKL 15 24GANILRGGL 14 27 ILRGGLSEI 14 28 LRGGLSEIV 14 38 PIEWQQDRK 14 113ANSWRNPVL 14 116 WRNPVLPHT 14 139 KSQAASGTL 14 141 QAASGTLSL 14 143ASGTLSLAF 14 173 LSKLTQEQK 14 13 LASPAAAWK 13 31 GLSEIVLPI 13 44DRKIPPLST 13 109 ALKAANSWR 13 122 PHTNGVGPL 13 148 SLAFTSWSL 13 151FTSWSLGEF 13 159 FLGSGTWMK 13 165 WMKLETIIL 13 176 LTQEQKSKH 13 181KSKHCMFSL 13 39 IEWQQDRKI 12 102 PPESPDRAL 12 103 PESPDRALK 12 130LWEFLLRLL 12 136 RLLKSQAAS 12 163 GTWMKLETI 12 178 QEQKSKHCM 12 19AWKCLGANI 11 45 RKIPPLSTP 11 50 LSTPPPPAM 11 108 RALKAANSW 11 115SERNPVLPH 11 127 VGPLWEFLL 11 152 TSWSLGEFL 11 157 GEFLGSGTW 11 164TWMKLETII 11 179 EQKSKHCMF 11 15 SPAAAWKCL 10 30 GGLSEIVLP 10 76NKSSSSSQI 10 92 EDDEAQDSI 10 75 RNKSSSSSQ 8 85 PVVGVVTED 8 145 GTLSLAFTS8 171 IILSKLTQE 8 185 CMFSLISGS 8

TABLE XXX V8-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 EGMGGTIPH 13 1 KSQFLEEGM 11 5LEEGMGGTI  9 8 GMGGTIPHV  9

TABLE XXX V13-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 PKSLSETFL 14 1 SPKSLSETF 13 9FLPNGINGI 12 6 SETFLPNGI  8 7 ETFLPNGTN  6 8 TFLPNGING  6

TABLE XXX V14-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 LRLFTFWRG 15 1 NLPLRLFTF 13 3PLRLFTFWR 11 5 RLFTFWRGP  7

TABLE XXX V21-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 KLTQEQKTK 18 3 LTQEQKTKH 14 8KTKHCMFSL 13 5 QEQKTKHCM 11 6 EQKTKHCMF 11

TABLE XXX V25-HLA-B2705-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 LFLPCISQK 18 5 PCISQKLKR 16 7ISQKLKRIK 15 8 SQKLKRIKK 15 3 FLPCISQKL 14 4 LPCISQKLK 13 6 CISQKLKRI 129 QKLKRIKKG  9 1 ILFLPCISQ  8

TABLE XXXI V1-HLA-B2709-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 326 RRSERYLFL 25 198 AREIENLPL 22 424YRFYTPPNF 22 212 WRGPVVVAI 21 28 ARKVTVGVI 20 50 IRCGYHVVI 20 325MRRSERYLF 20 104 LRHLLVGKI 19 182 ARQLNFIPI 19 355 WRIEMYISF 18 274GLLAAAYQL 18 289 RRFPPWLET 18 105 RHLLVGKIL 16 193 GSLSSAREI 15 214GPVVVAISL 15 441 IVILDLLQL 15 37 GSGDFAKSL 14 39 GDFAKSLTI 14 48RLIRCGYHV 14 264 ITLLSLVYL 14 306 GLLSFFFAM 14 313 AMVHVAYSL 14 425RFYTPPNFV 14 430 PNFVLALVL 14 436 LVLPSIVIL 14 47 IRLIRGGYH 13 61RNPKFASEF 13 68 EFFPHVVDV 13 99 TSLWDLRHL 13 135 SLFPDSLIV 13 148VVSAWALQL 13 177 QVIELARQL 13 179 IELARQLNF 13 206 LRLFTLWRG 13 220ISLATFFFL 13 287 KYRRFPPWL 13 297 TWLQCRKQL 13 302 RKQLGLLSF 13 396STLGYVALL 13 41 FAKSLTIRL 12 85 KTNIIFVAI 12 96 EHYTSLWDL 12 114IDVSNNMRI 12 120 MRTNQYPES 12 125 YPESNAEYL 12 146 FNVVSAWAL 12 157GPKDASRQV 12 159 KDASRQVYI 12 200 EIENLPLRL 12 223 ATFFFLYSF 12 227FLYSFVRDV 12 232 VRDVIHPYA 12 261 IVAITLLSL 12 267 LSLVYLAGL 12 268SLVYLAGLL 12 303 KQLGLLSFF 12 315 VHVAYSLCL 12 317 VAYSLCLPM 12 329ERYLFLNMA 12 365 IMSLGLLSL 12 366 MSLGLLSLL 12 395 QSTLGYVAL 12 403LLISTFHVL 12 416 KRAFEEEYY 12 426 FYTPPNFVL 12 428 TPPNFVLAL 12 439PSIVILDLL 12

TABLE XXXI V2-HLA-B2709-9mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 GLQALSLSL 14 3 SPGLQALSL 12 15SGFTPFSCL 12 1 SGSPGLQAL 11 9 LSLSLSSGF 11 17 FTPFSCLSL 11 31 YRCPPPCPA11 35 PPCPADFFL 11 12 SLSSGFTPF 9 33 CPPPCPADF 9 34 PPPCPADFF 9 37CPADFFLYF 9 32 RCPPPCPAD 6

TABLE XXXI V5A-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 LRLFTFWRG 13 7 FTFWRGPVV 11 6LFTFWRGPV 9 8 TFWRGPVVV 9 1 NLPLRLFTF 8 5 RLFTFWRGP 6

TABLE XXXI V5B-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 WREFSFIQI 19 2 REFSFIQIF 15 14ADTQTELEL 13 20 LELEFVFLL 13 22 LEFVFLLTL 13 24 FVFLLTLLL 13 19ELELEFVFL 11 23 EFVFLLTLL 11 5 SFIQIFCSF 10 12 SFADTQTEL 10 16 TQTELELEF10 18 TELELEFVF 10

TABLE XXXI V6-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 7 ILGKIILFL 13 23 KRIKKGWEK 13 5IVILGKIIL 12 10 KIILFLPCI 12 27 KGWEKSQFL 12 38 GIGGTIPHV 12 14FLPCISRKL 11 26 KKGWEKSQF 11 3 PSIVILGKI 10 6 VILGKIILF 10 19 SRKLKRIKK10 31 KSQFLEEGI 10 43 IPHVSPERV 10 45 HVSPERVTV 10 4 SIVILGKII 9 17CISRKLKRI 9 35 LEEGIGGTI 9 46 VSPERVTVM 9 20 RKLKRIKKG 6 41 GTIPHVSPE 6

TABLE XXXI V7A-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 PKSLSETFL 10 1 SPKSLSETF 9 6 SETFLPNGI9 9 FLPNGINGI 8 3 KSLSETFLP 5 8 TFLPNGING

TABLE XXXI V7B-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 9 STLGYVALL 13 8 QSTLGYVAL 12 3NMAYQQSTL 10 6 YQQSTLGYV 9

TABLE XXXI V7C-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 28 LRGGLSEIV 18 29 RGGLSEIVL 14 31GLSEIVLPI 14 126 GVGPLWEFL 14 24 GANILRGGL 13 5 ILDLSVEVL 12 107DRALKAANS 12 113 ANSWRNPVL 12 116 WRNPVLPHT 12 122 PHTNGVGPL 12 129PLWEFLLRL 12 135 LRLLKSQAA 12 139 KSQAASGTL 12 141 QAASGTLSL 12 168LETIILSKL 12 181 KSKHCMFSL 12 4 VILDLSVEV 11 20 WKCLGANIL 11 42QQDRKIPPL 11 44 DRKIPPLST 11 50 LSTPPPPAM 11 74 IRNKSSSSS 11 82SQIPVVGVV 11 102 PPESPDRAL 11 119 PVLPHTNGV 11 152 TSWSLGEFL 11 163GTWMKLETI 11 2 SIVILDLSV 10 15 SPAAAWKCL 10 19 AWKCLGANI 10 76 NKSSSSSQI10 79 SSSSQIPVV 10 81 SSQIPVVGV 10 112 AANSWRNPV 10 127 VGPLWEFLL 10 130LWEFLLRLL 10 143 ASGTLSLAF 10 148 SLAFTSWSL 10 158 EFLGSGTWM 10 160LGSGTWMKL 10 165 WMKLETIIL 10 27 ILRGGLSEI 9 39 IEWQQDRKI 9 78 SSSSSQIPV9 125 NGVGPLWEF 9 179 EQKSKHCMF 9 66 TAEAQESGI 8 92 EDDEAQDSI 8 151FTSWSLGEF 8 164 TWMKLETII 8 178 QEQKSKHCM 8 182 SKHCMFSLI 8

TABLE XXXI V8-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 GMGGTIPHV 12 1 KSQFLEEGM 10 5LEEGMGGTI 8

TABLE XXXI V13-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 PKSLSETFL 10 1 SPKSLSETF 9 6 SETFLPNGI9 9 FLPNGINGI 8 3 KSLSETFLP 5 8 TFLPNGING 4

TABLE XXXI V14-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 4 LRLFTFWRG 13 7 FTFWRGPVV 11 6LFTFWRGPV 9 8 TFWRGPVVV 9 1 NLPLRLFTF 8 5 RLFTFWRGP 6

TABLE XXXI V21-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 8 KTKHCMFSL 12 5 QEQKTKHCM 8 6 EQKTKHCMF8 9 TKHCMFSLI 8

TABLE XXXI V25-HLA-B2709- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 FLPCISQKL 11 6 CISQKLKRI 9 2 LFLPCISQK4

TABLE XXXII V1-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 352 EEVWRIEMY 26 201 IENLPLRLF 24 179IELARQLNF 23 14 SETCLPNGI 21 419 FEEEYYRFY 21 357 IEMYISFGI 20 42AKSLTIRLI 18 436 LVLPSIVIL 18 117 SNNMRINQY 17 144 KGFNVVSAW 17 259LPIVAITLL 17 441 IVILDLLQL 17 5 SMMGSPKSL 16 138 PDSLIVKGF 16 177QVIELARQL 16 199 REIENLPLR 16 203 NLPLRLFTL 16 219 AISLATFFF 16 223ATFFFLYSF 16 256 NKTLPIVAI 16 263 AITLLSLVY 16 290 RFPPWLETW 16 392SFIQSTLGY 16 403 LLISTFHVL 16 428 TPPNFVLAL 16 439 PSIVILDLL 16 67SEFFPHVVD 15 79 HEDALTKTN 15 100 SLWDLRHLL 15 130 AEYLASLFP 15 182ARQLNFIPI 15 196 SSAREIENL 15 200 EIENLPLRL 15 212 WRGPVVVAI 15 231FVRDVIHPY 15 252 IEIVNKTLP 15 297 TWLQCRKQL 15 363 FGIMSLGLL 15 378SIPSVSNAL 15 389 REFSFIQST 15 390 EFSFIQSTL 15 396 STLGYVALL 15 400YVALLISTF 15 421 EEYYRFYTP 15 430 PNFVLALVL 15 438 LPSIVILDL 15 17CLPNGINGI 14 37 GSGDFAKSL 14 82 ALTKTNIIF 14 85 KTNIIFVAI 14 96EHYTSLWDL 14 105 RHLLVGKIL 14 148 VVSAWALQL 14 198 AREIENLPL 14 204LPLRLFTLW 14 218 VAISLATFF 14 221 SLATFFFLY 14 258 TLPIVAITL 14 264ITLLSLVYL 14 272 LAGLLAAAY 14 303 KQLGLLSFF 14 313 AMVHVAYSL 14 351EEEVWRIEM 14 355 WRIEMYISF 14 360 YISFGIMSL 14 365 IMSLGLLSL 14 366MSLGLLSLL 14 383 SNALNWREF 14 385 ALNWREFSF 14 395 QSTLGYVAL 14 411LIYGWKRAF 14 426 FYTPPNFVL 14 435 ALVLPSIVI 14 28 ARKVTVGVI 13 46TIRLIRCGY 13 99 TSLWDLRHL 13 126 PESNAEYLA 13 129 NAEYLASLF 13 133LASLFPDSL 13 134 ASLFPDSLI 13 146 FNVVSAWAL 13 158 PKDASRQVY 13 180ELARQLNFI 13 184 QLNFIPIDL 13 240 ARNQQSDFY 13 251 PIEIVNKTL 13 253EIVNKTLPI 13 268 SLVYLAGLL 13 274 GLLAAAYQL 13 286 TKYRRFPPW 13 287KYRRFPPWL 13 302 RKQLGLLSF 13 311 FFAMVHVAY 13 323 LPMRRSERY 13 326RRSERYLFL 13 328 SERYLFLNM 13 330 RYLFLNMAY 13 341 VHANIENSW 13 347NSWNEEEVW 13 380 PSVSNALNW 13 407 TFHVLIYGW 13 418 AFEEEYYRF 13 420EEEYYRFYT 13 424 YRFYTPPNF 13 444 LDLLQLCRY 13 10 PKSLSETCL 12 39GDFAKSLTI 12 41 FAKSLTIRL 12 57 VIGSRNPKF 12 61 RNPKFASEF 12 75DVTHHEDAL 12 81 DALTKTNII 12 94 HREHYTSLW 12 125 YPESNAEYL 12 128SNAEYLASL 12 173 QARQQVIEL 12 187 FIPIDLGSL 12 214 GPVVVAISL 12 217VVAISLATF 12 220 ISLATFFFL 12 261 IVAITLLSL 12 267 LSLVYLAGL 12 280YQLYYGTKY 12 283 YYGTKYRRF 12 299 LQCRKQLGL 12 300 QCRKQLGLL 12 324PMRRSERYL 12 325 MRRSERYLF 12 350 NEEEVWRIE 12 353 EVWRIEMYI 12 362SFGIMSLGL 12 404 LISTFHVLI 12 405 ISTFHVLIY 12

TABLE XXXII V2-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 SGSPGLQAL 18 15 SGFTPFSCL 15 33CPPPCPADF 15 3 SPGLQALSL 14 23 LSLPSSWDY 14 12 SLSSGFTPF 13 21 SCLSLPSSW13 35 PPCPADFFL 13 36 PCPADFFLY 13 37 CPADFFLYF 13 17 FTPFSCLSL 12 34PPPCPADFF 12 5 GLQALSLSL 11 9 LSLSLSSGF 11

TABLE XXXII V5A-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 16 2 LPLRLFTFW 13

TABLE XXXII V5B-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 2 REFSFIQIF 25 22 LEFVFLLTL 25 20LELEFVFLL 23 18 TELELEFVF 22 5 SFIQIFCSF 16 24 FVFLLTLLL 16 19 ELELEFVFL15 14 ADTQTELEL 14 23 EFVFLLTLL 14 12 SFADTQTEL 12

TABLE XXXII V6-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 35 LEEGIGGTI 21 6 VILGKIILF 17 5IVILGKIIL 15 7 ILGKIILFL 15 21 KLKRIKKGW 15 3 PSIVILGKI 14 10 KIILFLPCI14 14 FLPCISRKL 14 17 CISRKLKRI 13 26 KKGWEKSQF 12 29 WEKSQFLEE 12 36EEGIGGTIP 12 4 SIVILGKII 11 27 KGWEKSQFL 11

TABLE XXXII V7A-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 6 SETFLPNGI 21 9 FLPNGINGI 14 1SPKSLSETF 12 2 PKSLSETFL 12

TABLE XXXII V7B-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 AYQQSTLGY 15 9 STLGYVALL 15 8QSTLGYVAL 14 3 NMAYQQSTL 12

TABLE XXXII V7C-HLA-B4402- 9mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 33 SEIVLPIEW 26 157 GEFLGSGTW 24 168LETIILSKL 23 39 IEWQQDRKI 20 143 ASGTLSLAF 17 51 STPPPPAMW 16 70QESGIRNKS 16 103 PESPDRALK 16 113 ANSWRNPVL 16 131 WEFLLRLLK 16 42QQDRKIPPL 15 5 ILDLSVEVL 14 61 EEAGATAEA 14 10 VEVLASPAA 13 12 VLASPAAAW13 15 SPAAAWKCL 13 20 WKCLGANIL 13 29 RGGLSEIVL 13 60 TEEAGATAE 13 67AEAQESGIR 13 91 TEDDEAQDS 13 102 PPESPDRAL 13 108 RALKAANSW 13 125NGVGPLWEF 13 126 GVGPLWEFL 13 127 VGPLWEFLL 13 130 LWEFLLRLL 13 146TLSLAFTSW 13 160 LGSGTWMKL 13 165 WMKLETIIL 13 31 GLSEIVLPI 12 122PHTNGVGPL 12 123 HTNGVGPLW 12 129 PLWEFLLRL 12 139 KSQAASGTL 12 141QAASGTLSL 12 151 FTSWSLGEF 12 179 EQKSKHCMF 12

TABLE XXXII V8-HLA-B4402-9mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 LEEGMGGTI 20 6 EEGMGGTIP 12

TABLE XXXII V13-HLA-B4402-9mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 6 SETFLPNGI 21 9 FLPNGINGI 14 1SPKSLSETF 12 2 PKSLSETFL 72

TABLE XXXII V14-HLA-B4402-9mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 1 NLPLRLFTF 16 2 LPLRLFTFW 13

TABLE XXXII V21-HLA-B4402-9mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 6 EQKTKHCMF 13 5 QEQKTKHCM 11 8KTKHCMFSL 11 9 TKHCMFSLI 10

TABLE XXXII V25-HLA-B4402-9mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 FLPCISQKL 13 6 CISQKLKRI 12 2LFLPCISQK 8 9 QKLKRIKKG 8

TABLE XXXIIII V1-HLA-B5101- 9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 3; each start position is specified, the length of peptide is9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 81 DALTKTNII 29 27 DARKVTVGV 2665 FASEFFPHV 23 374 LAVTSIPSV 23 434 LALVLPSIV 23 438 LPSIVILDL 22 246DFYKIPIEI 21 262 VAITLLSLV 21 368 LGLLSLLAV 21 428 TPPNFVLAL 21 429PPNFVLALV 21 23 NGIKDARKV 20 157 GPKDASRQV 20 214 GPVVVAISL 20 259LPIVAITLL 20 41 FAKSLTIRL 19 125 YPESNAEYL 19 133 LASLFPDSL 19 173QARQQVIEL 19 250 IPIEIVNKT 19 291 FPPWLETWL 19 50 IRCGYHVVI 18 228LYSFVRDVI 17 336 MAYQQVHAN 17 371 LSLLAVTSI 17 28 ARKVTVGVI 16 39GDFAKSLTI 16 70 FPHVVDVTH 16 104 LRHLLVGKI 16 141 LIVKGFNVV 16 160DASRQVYIC 16 204 LPLRLFTLW 16 227 FLYSFVRDV 16 237 HPYARNQQS 16 317VAYSLCLPM 16 52 CGYHVVIGS 15 137 FPDSLIVKG 15 164 QVYICSNNI 15 171NIQARQQVI 15 193 GSLSSAREI 15 210 TLWRGPVVV 15 212 WRGPVVVAI 15 276LAAAYQLYY 15 349 WNEEEVWRI 15 363 FGIMSLGLL 15 397 TLGYVALLI 15 425RFYTPPNFV 15 18 LPNGINGIK 14 25 IKDARKVTV 14 114 IDVSNNMRI 14 152WALQLGPKD 14 209 FTLWRGPVV 14 222 LATFFFLYS 14 242 NQQSDFYKI 14 258TLPIVAITL 14 278 AAYQLYYGT 14 379 IPSVSNALN 14 386 LNWREFSFI 14 398LGYVALLIS 14 401 VALLISTFH 14 404 LISTFHVLI 14 433 VLALVLPSI 14 435ALVLPSIVI 14

TABLE XXXIIII V2-HLA-B5101-9mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 3 SPGLQALSL 18 35 PPCPADFFL 16 15SGFTPFSCL 15 1 SGSPGLQAL 13 7 QALSLSLSS 13 18 TPFSCLSLP 13 25 LPSSWDYRC13 37 CPADFFLYF 13 33 CPPPCPADF 12 34 PPPCPADFF 12 17 FTPFSCLSL 10 4PGLQALSLS 9 5 GLQALSLSL 8

TABLE XXXIIII V5A-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 2 LPLRLFTFW 16 8 TFWRGPVVV 15 7FTFWRGPVV 13 6 LFTFWRGPV 10 9 FWRGPVVVA 8 4 LRLFTFWRG 7

TABLE XXXIIII V5B-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 20 LELEFVFLL 14 1 WREFSFIQI 1322 LEFVFLLTL 13 13 FADTQTELE 12 12 SFADTQTEL 9 17 QTELELEFV 9 24FVFLLTLLL 9 14 ADTQTELEL 8 18 TELELEFVF 8 19 ELELEFVFL 8 23 EFVFLLTLL 815 DTQTELELE 6

TABLE XXXIIII V6-HLA-B5101-9mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 43 IPHVSPERV 23 2 LPSIVILGK 16 27KGWEKSQFL 16 35 LEEGIGGTI 15 15 LPCISRKLK 14 17 CISRKLKRI 14 3 PSIVILGKI13 39 IGGTIPHVS 13 38 GIGGTIPHV 12 4 SIVILGKII 11 7 ILGKIILFL 11 10KIILFLPCI 11 14 FLPCISRKL 11 45 HVSPERVTV 11

TABLE XXXIIII V7A-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 9 FLPNGINGI 14 1 SPKSLSETF 12 6SETFLPNGI 12 2 PKSLSETFL

TABLE XXXIIII V7B-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 4 MAYQQSTLG 16 6 YQQSTLGYV 12 9STLGYVALL 12 3 NMAYQQSTL 9 8 QSTLGYVAL 7

TABLE XXXIIII V7C-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 66 TAEAQESGI 22 101 DPPESPDRA20 112 AANSWRNPV 19 15 SPAAAWKCL 18 160 LGSGTWMKL 18 29 RGGLSEIVL 17 84IPVVGVVTE 17 102 PPESPDRAL 17 141 QAASGTLSL 17 24 GANILRGGL 16 39IEWQQDRKI 16 31 GLSEIVLPI 15 68 EAQESGIRN 15 82 SQIPVVGVV 15 108RALKAANSW 15 149 LAFTSWSLG 15 163 GTWMKLETI 15 5 ILDLSVEVL 14 27ILRGGLSEI 14 37 LPIEWQQDR 14 47 IPPLSTPPP 14 48 PPLSTPPPP 14 54PPPAMWTEE 14 121 LPHTNGVGP 14 127 VGPLWEFLL 14 128 GPLWEFLLR 14 4VILDLSVEV 13 13 LASPAAAWK 13 18 AAWKCLGAN 13 52 TPPPPAMWT 13 53PPPPAMWTE 13 62 EAGATAEAQ 13 95 EAQDSIDPP 13 142 AASGTLSLA 13 164TWMKLETII 13 17 AAAWKCLGA 12 64 GATAEAQES 12 76 NKSSSSSQI 12 79SSSSQIPVV 12 92 EDDEAQDSI 12 105 SPDRALKAA 12 111 KAANSWRNP 12 118NPVLPHTNG 12 129 PLWEFLLRL 12 182 SKHCMFSLI 12 16 PAAAWKCLG 11 28LRGGLSEIV 11 56 PAMWTEEAG 11 81 SSQIPVVGV 11 119 PVLPHTNGV 11 168LETIILSKL 11 19 AWKCLGANI 10 23 LGANILRGG 10 30 GGLSEIVLP 10 55PPAMWTEEA 10 78 SSSSSQIPV 10 113 ANSWRNPVL 10 130 LWEFLLRLL 10

TABLE XXXIIII V8-HLA-B5101-9mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 9amino acids, and the end position for each peptide is the start positionplus eight. Pos 123456789 score 5 LEEGMGGTI 16 8 GMGGTIPHV 12 9MGGTIPHVS 12 7 EGMGGTIPH 8

TABLE XXXIIII V13-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 27; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 9 FLPNGINGI 14 1 SPKSLSETF 12 6SETFLPNGI 12 2 PKSLSETFL 8

TABLE XXXIIII V14-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 29; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 2 LPLRLFTFW 16 8 TFWRGPVVV 15 7FTFWRGPVV 13 6 LFTFWRGPV 10 9 FWRGPVVVA 8 4 LRLFTFWRG 7

TABLE XXXIIII V21-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 43; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 9 TKHCMFSLI 13 3 LTQEQKTKH 7 8KTKHCMFSL 6

TABLE XXXIIII V25-HLA-B5101-9mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 51; each start position is specified, the length of peptideis 9 amino acids, and the end position for each peptide is the startposition plus eight. Pos 123456789 score 4 LPCISQKLK 14 6 CISQKLKRI 14 3FLPCISQKL 10 9 QKLKRIKKG 7

TABLE XXXIV V1-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 351 EEEVWRIEMY 26 391 FSFIQSTLGY 26 418AFEEEYYRFY 26 443 ILDLLQLCRY 26 220 ISLATFEFLY 24 262 VAITLLSLVY 23 327RSERYLFLNM 23 45 LTIRLIRCGY 22 275 LLAAAYQLYY 22 404 LISTFHVLIY 22 116VSNNMRINQY 20 123 NQYPESNAEY 20 271 YLAGLLAAAY 19 279 AYQLYYGTKY 19 427YTPPNFVLAL 19 38 SGDFAKSLTI 18 274 GLLAAAYQLY 18 101 LWDLRHLLVG 17 157GPKDASRQVY 17 178 VIELARQLNF 17 230 SFVRDVIHPY 17 239 YARNQQSDFY 17 396STLGYVALLI 17 66 ASEFFPHVVD 16 89 IFVAIHREHY 16 94 HREHYTSLWD 16 129NAEYLASLFP 16 310 FFFAMVHVAY 16 322 CLPMRRSERY 16 329 ERYLFLNMAY 16 350NEEEVWRIEM 15 414 GWKRAFEEEY 15 415 WKRAEEEEYY 15 13 LSETCLPNGI 14 125YPESNAEYLA 14 244 QSDFYKIPIE 14 257 KTLPIVAITL 14 76 VTHHEDALTK 13 198AREIENLPLR 13 366 MSLGLLSLLA 13 420 EEEYYRFYTP 13 25 IKDARKVTVG 12 135SLFPDSLIVK 12 137 FPDSLIVKGF 12 200 EIENLPLRLF 12 221 SLATEFFLYS 12 251PIEIVNKTLP 12 268 SLVYLAGLLA 12 419 FEEEYYRFYT 12 439 PSIVILDLLQ 12

TABLE XXXIV V2-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 35 PPCPADFFLY 24 22 CLSLPSSWDY 16 28SWDYRCPPPC 12 2 GSPGLQALAL 11

TABLE XXXIV V5A-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 FTFWRGPVVV 8 1 ENLPLRLFTF 4 2NLPLRLFTFW 4 4 PLRLFTFWRG 4 10 FWRGPVVVAI 3

TABLE XXXIV V5B-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 14 FADTQTELEL 17 18 QTELELEFVF 17 22ELEFVFLLTL 17 20 ELELEFVFLL 14 16 DTQTELELEF 12 21 LELEFVFLLT 11 2WREFSFIQIF 10 5 FSFIQIFCSF 8 24 EFVFLLTLLL 8

TABLE XXXIV V6-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 29 GWEKSQFLEE 19 35 FLEEGIGGTI 13 36LEEGIGGTIP 12 1 LVLPSIVILG 11 19 ISRKLKRIKK 11 42 GTIPHVSPER 10 9LGKIILFLPC 9

TABLE XXXIV V7A-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 LSETELPNGI 14 4 KSLSETFLPN 13 8ETFLPNGING 11

TABLE XXXIV V7B-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 MAYQQSTLGY 21 10 STLGYVALLI 17

TABLE XXXIV V7C-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 131 LWEFLLRLLK 19 33 LSEIVLPIEW 18 91VTEDDEAQDS 17 60 WTEEAGATAE 16 100 SIDPPESPDR 16 70 AQESGIRNKS 14 94DDEAQDSIDP 14 6 ILDLSVEVLA 13 103 PPESPDRALK 13 124 HTNGVGPLWE 13 168KLETIILSKL 13 10 SVEVLASPAA 12 39 PIEWQQDRKI 12 43 QQDRKIPPLS 12 52STPPPPAMWT 12 104 PESPDRALKA 12 106 SPDRALKAAN 12 128 VGPLWEFLLR 12 170ETIILSKLTQ 12 97 AQDSIDPPES 11 115 NSWRNPVLPH 11 154 SWSLGEFLGS 11 2PSIVILDLSV 10 61 TEEAGATAEA 10 67 TAEAQESGIR 10 92 TEDDEAQDSI 10 93EDDEAQDSID 10 157 LGEFLGSGTW 10 162 GSGTWMKLET 10 178 TQEQKSKHCM 10 51LSTPPPPAMW 9 146 GTLSLAFTSW 9 182 KSKHCMFSLI 9

TABLE XXXIV V8-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 FLEEGMGGTI 13 6 LEEGMGGTIP 12

TABLE XXXIV V13-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 LSETFLPNGI 14 4 KSLSETFLPN 13 8ETFLPNGING 11

TABLE XXXIV V7C-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 FTFWRGPVVV 8 1 ENLPLRLFTF 4 2NLPLRLFTFW 4 4 PLRLFTFWRG 4 10 FWRGPVVVAI 3

TABLE XXXIV V21-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 9 KTKHCMIFSLI 11 5 TQEQKTKHCM 10 1LSKLTQEQKT 6 4 LTQEQKTKHC 6 10 TKHCMFSLIS 6

TABLE XXXIV V25-HLA-A1-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 ISQKLKRIKK 11 5 LPCISQKLKR 8 3LFLPCISQKL 6

TABLE XXXV V1-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 373 LLAVTSIPSV 31 266 LLSLVYLAGL 29 107LLVGKILIDV 28 367 SLGLLSLLAV 28 435 ALVLPSIVIL 28 364 GIMSLGLLSL 27 132YLASLFPDSL 26 370 LLSLLAVTSI 26 437 VLPSIVILDL 26 82 ALTKTNIIFV 25 100SLWDLRHLLV 25 140 SLIVKGFNVV 25 263 AITLLSLVYL 25 306 GLLSFFFAMV 25 402ALLISTFHVL 25 440 SIVILDLLQL 25 258 TLPIVAITLL 24 365 IMSLGLLSLL 24 403LLISTFHVLI 24 427 YTPPNFVLAL 24 24 GIKDARKVTV 23 48 RLIRCGYHVV 23 103DLRHLLVGKI 23 433 VLALVLPSIV 23 92 AIHREHYTSL 22 260 PIVAITLLSL 22 261IVAITLLSLV 22 298 WLQCRKQLGL 22 432 FVLALVLPSI 22 207 RLFTLWRGPV 21 210TLWRGPVVVA 21 257 KTLPIVAITL 21 385 ALNWREFSFI 21 49 LIRCGYHVVI 20 98YTSLWDLRHL 20 172 IQARQQVIEL 20 186 NFIPIDLGSL 20 219 AISLATFFFL 20 227FLYSFVRDVI 20 249 KIPIEIVNKT 20 253 EIVNKTLPIV 20 12 SLSETCLPNG 19 135SLFPDSLIVK 19 142 IVKGFNVVSA 19 197 SAREIENLPL 19 209 FTLWRGPVVV 19 211LWRGPVVVAI 19 271 YLAGLLAAAY 19 312 FAMVHVAYSL 19 396 STLGYVALLI 19 16TCLPNGINGI 18 65 FASEFFPHVV 18 67 SEFFPHVVDV 18 113 LIDVSNNMRI 18 359MYISFGIMSL 18 392 SFIQSTLGYV 18 106 HLLVGKILID 17 179 IELARQLNFI 17 202ENLPLRLFTL 17 250 IPIEIVNKTL 17 264 ITLLSLVYLA 17 269 LVYLAGLLAA 17 348SWNEEEVWRI 17 361 ISFGIMSLGL 17 369 GLLSLLAVTS 17 401 VALLISTFHV 17 26KDARKVTVGV 16 41 FAKSLTIRLI 16 111 KILIDVSNNM 16 112 ILIDVSNNMR 16 127ESNAEYLASL 16 195 LSSAREIENL 16 223 ATFFFLYSFV 16 226 FFLYSFVRDV 16 268SLVYLAGLLA 16 299 LQGRKQLGLL 16 356 RIEMYISFGI 16 362 SFGIMSLGLL 16 377TSIPSVSNAL 16 428 TPPNIFVLALV 16 434 LALVLPSIVI 16 438 LPSIVILDLL 16 443ILDLLQLCRY 16 27 DARKVTVGVI 15 36 IGSGDFAKSL 15 44 SLTIRLIRCG 15 47IRLIRCGYHV 15 147 NVVSAWALQL 15 166 YICSNNIQAR 15 189 PIDLGSLSSA 15 199REIENLPLRL 15 221 SLATFFFLYS 15 255 VNKTLPIVAI 15 273 AGLLAAAYQL 15 275LLAAAYQLYY 15 314 MVHVAYSLCL 15 335 NMAYQQVHAN 15 336 MAYQQVHANI 15 345IENSWNEEEV 15 394 IQSTLGYVAL 15 395 QSTLGYVALL 15 404 LISTFHVLIY 15 411LIYGWKRAFE 15

TABLE XXXV V2-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 2 GSPGLQALSL 16 5 GLQALSLSLS 15 16GFTPFSCLSL 15 10 SLSLSSGFTP 14 8 ALSLSLSSGF 13 12 SLSSGFTPFS 13 24SLPSSWDYRC 13 4 PGLQALSLSL 12 7 QALSLSLSSG 12 14 SSGFTPFSCL 11 22CLSLPSSWDY 10 9 LSLSLSSGFT 8 17 FTPFSCLSLP 8 6 LQALSLSLSS 7 34PPPCPADFFL 7

TABLE XXXV V5A-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 RLFTFWRGPV 21 8 FTFWRGPVVV 18 10FWRGPVVVAI 18 7 LFTFWRGPVV 11 9 TFWRGPVVVA 11 2 NLPLRLFTFW 10

TABLE XXXV V5B-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 22 ELEFVFLLTL 22 20 ELELEFVFLL 20 14FADTQTELEL 18 23 LEFVFLLTLL 17 19 TELELEFVFL 16 17 TQTELELEFV 15 12CSFADTQTEL 13 9 QIFCSFADTQ 11 21 LELEFVFLLT 11 1 NWREFSFIQI 10 7FIQIFCSFAD 10

TABLE XXXV V6-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 7 VILGKIILFL 28 35 FLEEGIGGTI 22 5SIVILGKIIL 20 14 LFLPCISRKL 18 43 TIPHVSPERV 18 2 VLPSIVILGK 17 13ILFLPCISRK 17 3 LPSIVILGKI 16 8 ILGKIILFLP 16 10 GKIILFLPCI 16 38EGIGGTIPHV 16 1 LVLPSIVILG 14 46 HVSPERVTVM 14 12 IILFLPCISR 13 34QFLEEGIGGT 13

TABLE XXXV V7A-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 SLSETFLPNG 19 9 TFLPNGINGI 18 2SPKSLSETFL 11 6 LSETFLPNGI 11 10 FLPNGINGIK 11

TABLE XXXV V7B-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 10 STLGYVALLI 19 2 FLNMAYQQST 18 6AYQQSTLGYV 16 3 LNMAYQQSTL 15 9 QSTLGYVALL 15 8 QQSTLGYVAL 13 4NMAYQQSTLG 9

TABLE XXXV V7C-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 VILDLSVEVL 26 168 KLETIILSKL 26 27NILRGGLSEI 24 28 ILRGGLSEIV 24 130 PLWEFLLRLL 24 160 FLGSGTWMKL 23 4IVILDLSVEV 22 66 ATAEAQESGI 19 81 SSSQIPVVGV 19 156 SLGEFLGSGT 19 6ILDLSVEVLA 18 32 GLSEIVLPIE 18 112 KAANSWRNPV 18 113 AANSWRNPVL 18 129GPLWEFLLRL 18 8 DLSVEVLASP 17 19 AAWKCLGANI 17 79 SSSSSQIPVV 17 127GVGPLWEFLL 17 134 FLLRLLKSQA 17 135 LLRLLKSQAA 17 141 SQAASGTLSL 17 31GGLSEIVLPI 16 42 WQQDRKIPPL 16 58 AMWTEEAGAT 16 82 SSQIPVVGVV 16 84QIPVVGVVTE 16 122 LPHTNGVGPL 16 137 RLLKSQAASG 16 138 LLKSQAASGT 16 148LSLAFTSWSL 16 13 VLASPAAAWK 15 23 CLGANILRGG 15 24 LGANILRGGL 15 152FTSWSLGEFL 15 163 SGTWMKLETI 15 3 SIVILDLSVE 14 29 LRGGLSEIVL 14 39PIEWQQDRKI 14 121 VLPHTNGVGP 14 139 LKSQAASGTL 14 142 QAASGTLSLA 14 164GTWMKLETII 14 171 TIILSKLTQE 14 172 IILSKLTQEQ 14 18 AAAWKCLGAN 13 50PLSTPPPPAM 13 100 SIDPPESPDR 13 149 SLAFTSWSLG 13 2 PSIVILDLSV 12 20AWKCLGANIL 12 47 KIPPLSTPPP 12 52 STPPPPAMWT 12 83 SQIPVVGVVT 12 102DPPESPDRAL 12 119 NPVLPHTNGV 12 126 NGVGPLWEFL 12 144 ASGTLSLAFT 12 173ILSKLTQEQK 12 176 KLTQEQKSKH 12 181 QKSKHCMFSL 12

TABLE XXXV V8C-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 FLEEGMGGTI 22 8 EGMFFTIPHV 15 9GMGGTIPHVS 12

TABLE XXXV V13-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 SLSETFLPNG 19 9 TFLPNGINGI 18 2SPKSLSETFL 11 6 LSETFLPNGI 11 10 FLPNGINGIK 11

TABLE XXXV V14-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 RLFTFWRGPV 21 8 FTFWRGPVVV 18 10 FWRGPVVVAI 18 7 LFTFWRGPVV 11 9 TFWRGPVVVA 11 2 NLPLRLFTFW 10

TABLE XXXV V21-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 3 KLTQEQKTKH 12 9 KTKHCMFSLI 12 8QKTKHCMFSL 11 1 LSKLTQEQKT 7 4 LTQEQKTKHC 7 2 SKLTQEQKTK 5

TABLE XXXV V25-HLA-A0201-10mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 3 LFLPCISQKL 18 2 ILFLPCISQK 17 1IILFLPCISQ 13 4 FLPCISQKLK 10 6 PCISQKLKRI 10 7 CISQKLKRIK  8

TABLE XXXVI V1-HLA-A0203-10mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 270 VYLAGLLAAA 27 269 LVYLAGLLAA 19 144KGFNVVSAWA 18 271 YLAGLLAAAY 17

TABLE XXXVI V2-HLA-A0203-10mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 30 DYRCPPPCPA 10  31 YRCPPPCPAD 9  1SGSPGLQALS 8 32 RCPPPCPADF 8

TABLE XXXVI V5A-HLA-A0203-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score  9 TFWRGPVVVA 10 10 FWRGPVVVAI  9

TABLE XXXVI V5B-HLA-A0203-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 SFIQIFCSFA 10  7 FIQIFCSFAD 9 8IQIFCSFADT 8

TABLE XXXVI V6-HLA-A0203-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XXXVI V7A-HLA-A0203-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XXXVI V7B-HLA-A0203-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 7 YQQSTLGYVA 10  8 QQSTLGYVAL 9 9QSTLGYVALL 8

TABLE XXXVI V7C-HLA-A0203-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 11 VEVLASPAAA 27 10 SVEVLASPAA 19 105ESPDRALKAA 19 135 LLRLLKSQAA 19 57 PAMWTEEAGA 18 59 MWTEEAGATA 18 61TEEAGATAEA 18 12 EVLASPAAAW 17 106 SPDRALKAAN 17 136 LRLLKSQAAS 17

TABLE XXXVI V8-HLA-A0203-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XXXVI V13-HLA-A0203-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XXXVI V14-HLA-A0203-10mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 10amino acids, ad the end position for each peptide is the start positionplus nine. Pos 1234567890 score  9 TFWRGPVVVA 10 10 FWRGPVVVAI  9

TABLE XXXVI V21-HLA-A0203-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XXXVI V25-HLA-A0203-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XXXVII V1-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 135 SLFPDSLIVK 28 34 GVIGSGDFAK 26 271YLAGLLAAAY 26 48 RLIRCGYHVV 24 21 GINGIKDARK 23 216 VVVAISLATF 23 369GLLSLLAVTS 23 17 CLPNGINGIK 22 55 HVVIGSRNPK 22 275 LLAAAYQLYY 22 278AAYQLYYGTK 22 307 LLSFFFAMVH 22 112 ILIDVSNNMR 21 142 IVKGFNVVSA 21 155QLGPKDASRQ 21 210 TLWRGPVVVA 21 76 VTHHEDALTK 20 217 VVAISLATFF 20 248YKIPIEIVNK 20 274 GLLAAAYQLY 20 281 QLYYGTKYRR 20 294 WLETWLQCRK 20 402ALLISTFHVL 20 2 ESISMMGSPK 19 49 LIRCGYHVVI 19 56 VVIGSRNPKF 19 102WDLRHLLVGK 19 147 NVVSAWALQL 19 227 FLYSFVRDVI 19 269 LVYLAGLLAA 19 375AVTSIPSVSN 19 443 ILDLLQLCRY 19 24 GIKDARKVTV 18 140 SLIVKGFNVV 18 333FLNMAYQQVH 18 410 VLIYGWKRAF 18 411 LIYGWKRAFE 18 435 ALVLPSIVIL 18 442VILDLLQLCR 18 46 TIRLIRCGYH 17 92 AIHREHYTSL 17 164 QVYICSNNIQ 17 177QVIELARQLN 17 254 IVNKTLPIVA 17 261 IVAITLLSLV 17 268 SLVYLAGLLA 17 331YLFLNMAYQQ 17 400 YVALLISTFH 17 403 LLISTFHVLI 17 404 LISTFHVLIY 17 30KVTVGVIGSG 16 123 NQYPESNAEY 16 141 LIVKGFNVVS 16 178 VIELARQLNF 16 207RLFTLWRGPV 16 234 DVIHPYARNQ 16 262 VAITLLSLVY 16 263 AITLLSLVYL 16 265TLLSLVYLAG 16 306 GLLSFFFAMV 16 322 CLPMRRSERY 16 340 QVHANIENSW 16 367SLGLLSLLAV 16 385 ALNWREFSFI 16 432 FVLALVLPSI 16 433 VLALVLPSIV 16 440SIVILDLLQL 16 441 IVILDLLQLC 16 32 TVGVIGSGDF 15 100 SLWDLRHLLV 15 106HLLVGKILID 15 121 RINQYPESNA 15 153 ALQLGPKDAS 15 187 FIPIDLGSLS 15 221SLATFFFLYS 15 235 VIHPYARNQQ 15 257 KTLPIVAITL 15 260 PIVAITLLSL 15 320SLCLPMRRSE 15 372 SLLAVTSIPS 15 393 FIQSTLGYVA 15 436 LVLPSIVILD 15 60SRNPKFASEF 14 88 IIFVAIHREH 14 103 DLRHLLVGKI 14 108 LVGKILIDVS 14 111KILIDVSNNM 14 132 YLASLFPDSL 14 150 SAWALQLGPK 14 171 NIQARQQVIE 14 180ELARQLNFIP 14 189 PIDLGSLSSA 14 190 IDLGSLSSAR 14 205 PLRLFTLWRG 14 215PVVVAISLAT 14 231 FVRDVIHPYA 14 266 LLSLVYLAGL 14 279 AYQLYYGTKY 14 316HVAYSLCLPM 14 370 LLSLLAVTSI 14 45 LTIRLIRCGY 13 75 DVTHHEDALT 13 82ALTKTNIIFV 13 128 SNAEYLASLF 13 154 LQLGPKDASR 13 157 GPKDASRQVY 13 166YICSNNIQAR 13 191 DLGSLSSARE 13 200 EIENLPLRLF 13 204 LPLRLFTLWR 13 240ARNQQSDFYK 13 298 WLQCRKQLGL 13 304 QLGLLSFFFA 13 310 FFFAMVHVAY 13 314MVHVAYSLCL 13 321 LCLPMRRSER 13 329 ERYLFLNMAY 13 353 EVWRIEMYIS 13 364GIMSLGLLSL 13 373 LLAVTSIPSV 13 397 TLGYVALLIS 13 399 GYVALLISTF 13 409HVLIYGWKRA 13 437 VLPSIVILDL 13 445 DLLQLCRYPD 13

TABLE XXXVII V2-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 ALSLSLSSGF 21 10 SLSLSSGFTP 19 22CLSLPSSWDY 17 5 GLQALSLSLS 15 32 RCPPPCPADF 15 12 SLSSGFTPFS 11 24SLPSSWDYRC 11 2 GSPGLQALSL 10 33 CPPPCPADFF 10

TABLE XXXVII V5A-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 RLFTFWRGPV 16 4 PLRLFTFWRG 14 1ENLPLRLFTF 13 2 NLPLRLFTFW 12 9 TFWRGPVVVA 11 3 LPLRLFTFWR 10 10 FWRGPVVVAI 10 8 FTFWRGPVVV  9 7 LFTFWRGPVV  7

TABLE XXXVII V5B-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 9 QIFCSEADTQ 17 22 ELEFVFLLTL 17 18QTELELEFVF 11 20 ELELEFVFLL 11 7 FIQIFCSFAD 10 8 IQIFCSFADT 8

TABLE XXXVII V6-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 13 ILFLPCISRK 26 2 VLPSIVILGK 23 15FLPCISRKLK 21 18 CISRKLKRIK 21 6 IVILGKIILF 20 22 KLKRIKKGWE 19 35FLEEGIGGTI 19 12 IILFLPCISR 18 46 HVSPERVTVM 18 23 LKRIKKGWEK 17 11KIILFLPCIS 16 19 ISRKLKRIKK 16 1 LVLPSIVILG 15 7 VILGKIILFL 15 25RIKKGWEKSQ 15 26 IKKGWEKSQF 15 39 GIGGTIPHVS 15 8 ILGKIILFLP 12

TABLE XXXVII V7A-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 10 FLPNGINGIK 22  5 SLSETFLPNG 12

TABLE XXXVII V7B-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 MAYQQSTLGY 13  2 FLNMAYQQST 12  10 STLGYVALLI 11  3 LNMAYQQSTL 9 7 YQQSTLGYVA 7 8 QQSTLGYVAL 7 1 LFLNMAYQQS6 9 QSTLGYVALL 6

TABLE XXXVII V7C-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 13 VLASPAAAWK 28 173 ILSKLTQEQK 25 137RLLKSQAASG 24 12 EVLASPAAAW 21 134 FLLRLLKSQA 21 4 IVILDLSVEV 20 36IVLPIEWQQD 20 120 PVLPHTNGVG 20 176 KLTQEQKSKH 20 83 SQIPVVGVVT 18 84QIPVVGVVTE 18 156 SLGEFLGSGT 18 167 MKLETIILSK 18 3 SIVILDLSVE 17 6ILDLSVEVLA 17 28 ILRGGLSEIV 17 74 GIRNKSSSSS 17 90 VVTEDDEAQD 17 121VLPHTNGVGP 17 138 LLKSQAASGT 17 27 NILRGGLSEI 16 100 SIDPPESPDR 16 110ALKAANSWRN 16 168 KLETIILSKL 16 171 TIILSKLTQE 16 5 VILDLSVEVL 15 8DLSVEVLASP 15 26 ANILRGGLSE 15 37 VLPIEYQQDR 15 135 LLRLLKSQAA 15 147TLSLAFTSWS 15 149 SLAFTSWSLG 15 159 EFLGSGTWMK 15 175 SKLTQEQKSK 15 38LPIEWQQDRK 14 47 KIPPLSTPPP 14 103 PPESPDRALK 14 109 RALKAANSWR 14 131LWEFLLRLLK 14 127 GVGPLWEFLL 13 143 AASGTLSLAF 13

TABLE XXXVII V8-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQ IDNO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 FLEEGMGGTI 19

TABLE XXXVII V13-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 10 FLPNGINGIK 22  5 SLSETFLPNG 12

TABLE XXXVII V14-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 RLFTFWRGPV 16 4 PLRLFTFWRG 14 1ENLPLRLFTF 13 2 NLPLRLFTFW 12 9 TFWRGPVVVA 11 3 LPLRLFTFWR 10 10 FWRGPVVVAI 10 8 FTFWRGPVVV  9 7 LFTFWRGPVV  7

TABLE XXXVII V21-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 3 KLTQEQKTKH 18 2 SKLTQEQKTK 17

TABLE XXXVII V25-HLA-A3-10mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 2 ILFLPCISQK 29 4 FLPCISQKLK 20 7CISQKLKRIK 18 1 IILFLPCISQ 14

TABLE XXXVII V1-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 216 VVVAISLATF 27 296 ETWLQCRKQL 27 200EIENLPLRLF 26 147 NVVSAWALQL 25 351 EEEVWRIEMY 25 202 ENLPLRLFTL 24 56VVIGSRNPKF 23 127 ESNAEYLASL 23 427 YTPPNFVLAL 23 440 SIVILDLLQL 23 45LTIRIIRCGY 22 234 DVIHPYARNQ 22 253 EIVNKTLPIV 22 260 PIVAITLLSL 22 329ERYLFLNMAY 21 15 ETCLPNGING 20 32 TVGVIGSGDF 20 98 YTSLWDLRHL 20 353EVWRIEMYIS 20 68 EFFPHVVDVT 19 75 DVTHHEDALT 19 115 DVSNNMRINQ 19 186NFIPIDLGSL 19 230 SFVRDVIHPY 19 257 KTLPIVAITL 19 314 MVHVAYSLCL 19 364GIMSLGLLSL 19 404 LISTFHVLIY 19 217 VVAISLATFF 18 359 MYISFGIMSL 18 399GYVALLISTF 18 441 IVILDLLQLC 18 2 ESISMMGSPK 17 30 KVTVGVIGSG 17 40DFAKSLTIRL 17 81 DALTKTNIIF 17 263 AITLLSLVYL 17 406 STFHVLIYGW 17 177QVIELARQLN 16 215 PVVVAISLAT 16 269 LVYLAGLLAA 16 435 ALVLPSIVIL 16 436LVLPSIVILD 16 34 GVIGSGDFAK 15 72 HVVDVTHHED 15 116 VSNNMRINQY 15 142IVKGFNVVSA 15 199 REIENLPLRL 15 250 IPIEIVNKTL 15 261 IVAITLLSLV 15 262VAITLLSLVY 15 310 FFFAMVHVAY 15 377 TSIPSVSNAL 15 389 REFSFIQSTL 15 391FSFIQSTLGY 15 432 FVLALVLPSI 15 31 VTVGVIGSGD 14 55 HVVIGSRNPK 14 89IFVAIHREHY 14 103 DLRHLLVGKI 14 108 LVGKILIDVS 14 148 VVSAWALQLG 14 222LATFFFLYSF 14 301 CRKQLGLLSF 14 352 EEVWRIEMYI 14 362 SFGIMSLGLL 14 417RAFEEEYYRF 14 437 VLPSIVILDL 14 443 ILDLLQLCRY 14 27 DARKVTVGVI 13 74VDVTHHEDAL 13 92 AIHREHYTSL 13 137 FPDSLIVKGF 13 172 IQARQQVIEL 13 176QQVIELARQL 13 178 VIELARQLNF 13 218 VAISLATFFF 13 223 ATFFFLYSFV 13 258TLPIVAITLL 13 299 LQCRKQLGLL 13 302 RKQLGLLSFF 13 358 EMYISFGIMS 13 361ISFGIMSLGL 13 365 IMSLGLLSLL 13 375 AVTSIPSVSN 13 376 VTSIPSVSNA 13 395QSTLGYVALL 13 410 VLIYGWKRAF 13

TABLE XXXVIII V2-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 17 FTPFSCLSLP 13 16 GFTPFSCLSL 12 35PPCPADFFLY 11 2 GSPGLQALSL 10 4 PGLQALSLSL 10 14 SSGFTPFSCL 10 22CLSLPSSWDY 10 8 ALSLSLSSGF 9 11 LSLSSGFTPF 9 32 RCPPPCPADF 9 33CPPPCPADFF 9 36 PCPADFFLYF 9 30 DYRCPPPCPA 8 34 PPPCPADFFL 8 7QALSLSLSSG 7 18 TPFSCLSLPS 7 3 SPGLQALSLS 6

TABLE XXXVIII V5A-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 1 ENLPLRLFTF 24 8 FTFWRGPVVV 12

TABLE XXXVIII V5B-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 16 DTQTELELEF 25 22 ELEFVFLLTL 24 24EFVFLLTLLL 23 20 ELELEFVFLL 22 18 QTELELEFVF 16 23 LEFVFLLTLL 16 4EFSFIQIFCS 14 5 FSFIQIFCSF 13 2 WREFSFIQIF 12 12 CSFADTQTEL 12

TABLE XXXVIII V6-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 IVILGKIILF 27 5 SIVILGKIIL 18 38EGIGGTIPHV 18 7 VILGKIILFL 17 1 LVLPSIVILG 16 46 HVSPERVTVM 15 42GTIPHVSPER 13

TABLE XXXVIII V7A-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 ETFLPNGING 24

TABLE XXXVIII V7B-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 9 QSTLGYVALL 13 5 MAYQQSTLGY 11 3LNMAYQQSTL 10 10  STLGYVALLI 10 8 QQSTLGYVAL  9

TABLE XXXVIII V7C-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 170 ETIILSKLTQ 24 12 EVLASPAAAW 21 35EIVLPIEWQQ 19 102 DPPESPDRAL 19 127 GVGPLWEFLL 19 5 VILDLSVEVL 17 152FTSWSLGEFL 17 69 EAQESGIRNK 16 105 ESPDRALKAA 16 89 EVVTEDDEAQ 15 133EFLLRLLKSQ 15 151 AFTSWSLGEF 15 3 SIVILDLSVE 14 4 IVILDLSVEV 14 45DRKIPPLSTP 14 86 PVVGVVTEDD 14 90 VVTEDDEAQD 14 99 DSIDPPESPD 14 130PLWEFLLRLL 14 168 KLETIILSKL 14 171 TIILSKLTQE 14 8 DLSVEVLASP 13 42WQQDRKIPPL 13 93 EDDEAQDSID 13 122 LPHTNGVGPL 13 125 TNGVGPLWEF 13 129GPLWEFLLRL 13 10 SVEVLASPAA 12 36 IVLPIEWQQD 12 72 ESGIRNKSSS 12 95DEAQDSIDPP 12 120 PVLPHTNGVG 12 126 NGVGPLWEFL 12 41 EWQQDRKIPP 11 60WTEEAGATAE 11 62 EEAGATAEAQ 11 63 EAGATAEAQE 11 66 ATAEAQESGI 11 96EAQDSIDPPE 11 141 SQAASGTLSL 11 159 EFLGSGTWMK 11 180 EQKSKHCMFS 11

TABLE XXXVIII V8-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 EGMGGTIPHV 14 7 EEGMGGTIPH 11 1EKSQFLEEGM 10 3 SQFLEEGMGG  6

TABLE XXXVIII V13-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 ETFLPNGING 24

TABLE XXXVIII V14-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 1 ENLPLRLFTF 24 8 FTFWRGPVVV 12

TABLE XXXVIII V21-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 4 LTQEQKTKHC 10 7 EQKTKHCMFS 10 8QKTKHCMFSL 10 6 QEQKTKHCMF 9 9 KTKHCMFSLI 9

TABLE XXXVIII V25-HLA-A26-10mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 2 ILFLPCISQK 10 3 LFLPCISQKL 10 6PCISQKLKRI 9 1 IILFLPCISQ 6 9 SQKLKRIKKG 6 7 GISQKLKRIK 4

TABLE XXXIX V1-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 429 PPNFVLALVL 23 438 LPSIVILDLL 22 9SPKSLSETCL 21 250 IPIEIVNKTL 21 323 LPMRRSERYL 21 137 FPDSLIVKGF 18 428TPPNFVLALV 17 125 YPESNAEYLA 16 214 GPVVVAISLA 16 219 AISLATFFFL 16 394IQSTLGYVAL 16 36 IGSGDFAKSL 15 197 SAREIENLPL 15 325 MRRSERYLFL 15 361ISFGIMSLGL 15 379 IPSVSNALNW 15 427 YTPPNFVLAL 15 211 LWRGPVVVAI 14 263AITLLSLVYL 14 402 ALLISTFHVL 14 435 ALVLPSIVIL 14 40 DFAKSLTIRL 13 92AIHREHYTSL 13 127 ESNAEYLASL 13 172 IQARQQVIEL 13 188 IPIDLGSLSS 13 195LSSAREIENL 13 199 REIENLPLRL 13 204 LPLRLFTLWR 13 259 LPIVAITLLS 13 260PIVAITLLSL 13 266 LLSLVYLAGL 13 290 RFPPWLETWL 13 364 GIMSLGLLSL 13 365IMSLGLLSLL 13 4 ISMMGSPKSL 12 18 LPNGINGIKD 12 70 FPHVVDVTHI 12 98YTSLWDLRHL 12 142 IVKGFNVVSA 12 147 NVVSAWALQL 12 157 GPKDASRQVY 12 202ENLPLRLFTL 12 257 KTLPIVAITL 12 273 AGLLAAAYQL 12 292 PPWLETWLQC 12 296ETWLQCRKQL 12 298 WLQCRKQLGL 12 314 MVHVAYSLCL 12 377 TSIPSVSNAL 12 395QSTLGYVALL 12 425 RFYTPPNFVL 12 437 VLPSIVILDL 12 440 SIVILDLLQL 12 26KDARKVTVGV 11 27 DARKVTVGVI 11 49 LIRCGYHVVI 11 62 NPKFASEFFP 11 74VDVTHHEDAL 11 95 REHYTSLWDL 11 99 TSLWDLRHLL 11 132 YLASLFPDSL 11 145GFNVVSAWAL 11 183 RQLNFIPIDL 11 186 NFIPIDLGSL 11 201 IENLPLRLFT 11 213RGPVVVAISL 11 237 HPYARNQQSD 11 252 IEIVNKTLPI 11 258 TLPIVAITLL 11 286TKYRRFPPWL 11 291 FPPWLETWLQ 11 312 FAMVHVAYSL 11 362 SFGIMSLGLL 11 389REFSFIQSTL 11

TABLE XXXIX V2-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 34 PPPCPADFFL 21 33 CPPPCPADFF 18 2GSPGLQALSL 14 16 GFTPFSCLSL 13 18 TPFSCLSLPS 13 4 PGLQALSLSL 12 14SSGFTPFSCL 12 25 LPSSWDYRCP 12 35 PPCPADFFLY 12 3 SPGLQALSLS 11 8ALSLSLSSGF 10 36 PCPADFFLYF 10

TABLE XXXIX V5A-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 10 FWRGPVVVAI 14 3 LPLRLFTFWR 11 9TFWRGPVVVA 10 6 RLFTFWRGPV 9 8 FTFWRGPVVV 9 1 ENLPLRLFTF 8 7 LFTFWRGPVV8

TABLE XXXIX V5B-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 19 TELELEFVFL 14 24 EFVFLLTLLL 14 14FADTQTELEL 13 22 ELEFVFLLTL 13 12 CSFADTQTEL 12 20 ELELEFVFLL 12 23LEFVFLLTLL 11 1 NWREFSFIQI 9 8 IQIFCSFADT 9 21 LELEFVFLLT 9 10IFCSFADTQT 8 16 DTQTELELEF 8 5 FSFIQIFCSF 7 6 SFIQIFCSFA 7 17 TQTELELEFV7 18 QTELELEFVF 7 2 WREESFIQIF 6

TABLE XXXIX V6-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 3 LPSIVILGKI 18 44 IPHVSPERVT 18 7VILGKIILFL 15 27 KKGWEKSQFL 13 16 LPCISRKLKR 12 46 HVSPERVTVM 12 14LFLPCISRKL 11 5 SIVILGKIIL 10 38 EGIGGTIPHV 10 26 IKKGWEKSQF 9 31EKSQFLEEGI 9 45 PHVSPERVTV 9

TABLE XXXIX V7A-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 2 SPKSLSETFL 22

TABLE XXXIX V7B-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 QQSTLGYVAL 15 3 LNMAYQQSTL 12 9QSTLGYVALL 12 10 STLGYVALLI 10 6 AYQQSTLGYV 8 7 YQQSTLGYVA 7

TABLE XXXIX V7C-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 122 LPHTNGVGPL 22 129 GPLWEFLLRL 22 102DPPESPDRAL 21 49 PPLSTPPPPA 18 55 PPPAMWTEEA 18 119 NPVLPHTNGV 17 141SQAASGTLSL 15 143 AASGTLSLAF 15 29 LRGGLSEIVL 14 113 AANSWRNPVL 14 15ASPAAAWKCL 13 48 IPPLSTPPPP 13 85 LPVVGVVTED 13 106 SPDRALKAAN 13 126NGVGPLWEFL 13 152 FTSWSLGEFL 13 165 TWMKLETIIL 13 181 QKSKHCMFSL 13 1LPSIVILDLS 12 5 VILDLSVEVL 12 16 SPAAAWKCLG 12 29 AWKCLGANIL 12 24LGANILRGGL 12 42 WQQDRKIPPL 12 54 PPPPAMWTEE 12 56 PPAMWTEEAG 12 103PPESPDRALK 12 127 GVGPLWEFLL 12 139 LKSQAASGTL 12 28 ILRGGLSEIV 11 44QDRKIPPLST 11 53 TPPPPAMWTE 11 81 SSSQIPVVGV 11 104 PESPDRALKA 11 144ASGTLSLAFT 11 148 LSLAFTSWSL 11 160 FLGSGTWMKL 11 168 KLETIILSKL 11 6ILDLSVEVLA 10 17 PAAAWKCLGA 10 19 AAWKCLGANI 10 31 GGLSEIVLPI 10 38LPIEWQQDRK 10 50 PLSTPPPPAM 10 78 KSSSSSQIPV 10 79 SSSSSQIPVV 10 83SQIPVVGVVT 10 112 KAANSWRNPV 10 130 PLWEFLLRLL 10

TABLE XXXIX V8-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 EGMGGTIPHV 11 1 EKSQFLEEGM 9 4QFLEEGMGGT 6 5 FLEEGMGGTI 6

TABLE XXXIX V13-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 2 SPKSLSETFL 22

TABLE XXXIX V14-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 10 FWRGPVVVAI 14 3 LPLRLFTFWR 11 9TFWRGPVVVA 10 6 RLFTFWRGPV 9 8 FTFWRGPVVV 9 1 ENLPLRLFTF 8 7 LFTFWRGPVV8

TABLE XXXIX V21-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 QKTKHGMFSL 11 9 KTKHCMFSLI 8 6QEQKTKHCMF 7 1 LSKLTQEQKT 6 5 TQEQKTKHCM 6

TABLE XXXIX V25-HLA-B0702-10mers-98P4B6 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 5 LPCISQKLKR 12 3 LFLPCISQKL 11 6PCISQKLKRI 6

TABLE XL V1-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V2-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V5A-HLA-B08-10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V5B-HLA-B08-10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V6-HLA-B08-10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V7A-HLA-B08-10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V7B-HLA-B08-10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V7C-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V8-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V13-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V14-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V21-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XL V25-HLA-B08- 10mers-98P4B6 Pos 1234567890 score NoResultsFound.

TABLE XLI V1-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V2-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V5A-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V5B-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V6-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7A-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7B-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7C-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V8-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V13-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V14-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V21-HLA-B1510- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V25-HLA-B1510-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V1-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V2-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V5A-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V5B-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V6-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7A-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7B-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7C-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V8-HLA-B2705-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V13-HLA-B2705- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V14-HLA-B2705- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V21-HLA-B2705- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V25-HLA-B2705- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V1-HLA-B2709- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V2-HLA-B2709- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V5A-HLA-B2709- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V5B-HLA-B2709- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V6-HLA-B2709- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7A-HLA-B2709- 10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7B-HLA-B2709-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V7C-HLA-B2709-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V8-HLA-B2709-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V13-HLA-B2709-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V14-HLA-B2709-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V21-HLA-B2709-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLI V25-HLA-B2709-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLIV V1-HLA-B4402-10mers-98P4B6 Each peptide is a portion of SEQID NO: 3; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 199 REIENLPLRL 25 351 EEEVWRIEMY 25 252IEIVNKTLPI 23 389 REFSFIQSTL 23 95 REHYTSLWDL 21 179 IELARQLNFI 21 352EEVWRIEMYI 20 79 HEDALTKTNI 19 377 TSLPSVSNAL 19 186 NFIPIDLGSL 18 202ENLPLRLFTL 18 257 KTLPIVAITL 18 427 YTPPNFVLAL 18 435 ALVLPSIVIL 18 273AGLLAAAYQL 17 289 RRFPPWLETW 17 296 ETWLQCRKQL 17 402 ALLISTFHVL 17 16TCLPNGINGI 16 116 VSNNMRINQY 16 200 EIENLPLRLF 16 219 AISLATFFFL 16 230SFVRDVIHPY 16 250 IPIEIVNKTL 16 262 VAITLLSLVY 16 263 AITLLSLVYL 16 359MYISFGIMSL 16 406 STFHVLIYGW 16 410 VLIYGWKRAF 16 36 IGSGDFAKSL 15 45LTIRLIRCGY 15 56 VVIGSRNPKF 15 60 SRNPKFASEF 15 67 SEFFPHVVDV iS 126PESNAEYLAS 15 130 AEYLASLFPD 15 203 NLPLRLFTLW 15 255 VNKTLPIVAI 15 258TLPIVAITLL 15 279 AYQLYYGTKY 15 310 FFFAMVHVAY 15 329 ERYLFLNMAY 15 394IQSTLGYVAL 15 437 VLPSIVILDL 15 4 ISMMGSPKSL 14 92 AIHREHYTSL 14 98YTSLWDLRHL 14 99 TSLWDLRHLL 14 123 NQYPESNAEY 14 137 FPDSLIVKGF 14 147NVVSAWALQL 14 183 RQLNFIPIDL 14 195 LSSAREIENL 14 218 VAISLATFFF 14 271YLAGLLAAAY 14 290 RFPPWLETWL 14 346 ENSWNEEEVW 14 361 ISFGIMSLGL 14 365IMSLGLLSLL 14 391 FSFIQSTLGY 14 396 STLGYVALLI i4 399 GYVALLISTF 14 404LISTFHVLIY 14 418 AFEEEYYRFY 14 420 EEEYYRFYTP 14 440 SIVILDLLQL 14 41FAKSLTIRLI 13 74 VDVTHHEDAL 13 80 EDALTKTNII 13 81 DALTKTNIIF 13 84TKTNIIFVAI 13 104 LRHLLVGKIL 13 127 ESNAEYLASL 13 128 SNAEYLASLF 13 143VKGFNVVSAW 13 145 GFNVVSAWAL 13 157 GPKDASRQVY 13 170 NNIQARQQVI 13 172IQARQQVIEL 13 176 QQVIELARQL 13 201 IENLPLRLFT 13 211 LWRGPVVVAI 13 213RGPVVVAISL 13 220 ISLATFFFLY 13 245 SDFYKIPIEI 13 266 LLSLVYLAGL 13 267LSLVYLAGLL 13 299 LQCRKQLGLL 13 303 KQLGLLSFFF 13 323 LPMRRSERYL 13 324PMRRSERYLF 13 328 SERYLFLNMA 13 350 NEEEVWRIEM 13 362 SFGIMSLGLL 13 364GIMSLGLLSL 13 379 IPSVSNALNW 13 384 NALNWREFSF 13 395 QSTLGYVALL 13 403LLISTFHVLI 13 429 PPNFVLALVL 13 438 LPSIVILDLL 13 443 ILDLLQLCRY 13 38SGDFAKSLTI 12 40 DFAKSLTIRL 12 93 IHREHYTSLW 12 105 RHLLVGKILI 12 124QYPESNAEYL 12 178 VIELARQLNE 12 192 LGSLSSAREI 12 197 SAREIENLPL 12 216VVVAISLATF 12 260 PIVAITLLSL 12 274 GLLAAAYQLY 12 282 LYYGTKYRRF 12 286TKYRRFPPWL 12 295 LETWLQCRKQ 12 301 CRKQLGLLSF 12 302 RKQLGLLSFF 12 312FAMVHVAYSL 12 357 IEMYISFGIM 12 385 ALNWREFSFI 12 417 RAFEEEYYRF 12 421EEYYRFYTPP 12 425 RFYTPPNFVL 12

TABLE XLIV V2-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 5; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 ALSLSLSSGF 15 32 RCPPPCPADF 15 33CPPPCPADFF 15 35 PPCPADFFLY 15 2 GSPGLQALSL 14 16 GFTPFSCLSL 14 36PCPADFFLYF 13 4 PGLQALSLSL 12 11 LSLSSGFTPF 12 14 SSGFTPFSCL 12 20FSCLSLPSSW 12 22 CLSLPSSWDY 12 34 PPPCPADFFL 11

TABLE XLIV V5A-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 1 ENLPLRLFTF 18 2 NLPLRLFTFW 14 10FWRGPVVVAI 13

TABLE XLIV V5B-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 11; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 23 LEFVFLLTLL 24 19 TELELEFVFL 23 20ELELEFVFLL 15 22 ELEFVFLLTL 15 24 EFVFLLTLLL 15 21 LELEFVFLLT 14 2WREFSFIQIF 13 3 REFSFIQIFC 13 5 FSFIQIFCSF 13 14 FADTQTELEL 13 1NWREFSFIQI 12 12 CSFADTQTEL 12 16 DTQTELELEF 12 18 QTELELEFVF 12

TABLE XLIV V6-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 13; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 IVILGKIILF 19 7 VILGKIILFL 16 14LFLPCISRKL 16 17 PCISRKLKRI 14 37 EEGIGGTIPH 14 4 PSIVILGKII 13 21RKLKRIKKGW 13 5 SIVILGKIIL 12 10 GKIILFLPCI 12 26 IKKGWEKSQF 12 3LPSIVILGKI 11 27 KKGWEKSQFL 11 30 WEKSQFLEEG 11 31 EKSQFLEEGI 11 36LEEGIGGTIP 11 35 FLEEGIGGTI 9 38 EGIGGTIPHV 9

TABLE XLIV V7A-HLA-B4402-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 9 TFLPNGINGI 16 1 GSPKSLSETF 12 2SPKSLSETFL 11 6 LSETFLPNGI 11 7 SETFLPNGIN 11

TABLE XLIV V7B-HLA-B4402-10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 8 QQSTLGYVAL 15 10  STLGYVALLI 14 9QSTLGYVALL 13 3 LNMAYQQSTL 12 5 MAYQQSTLGY 12

TABLE XLIV V7C-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 15; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 92 TEDDEAQDSI 20 179 QEQKSKHCMF 20 143AASGTLSLAF 18 34 SEIVLPIEWQ 17 104 PESPDRALKA 17 12 EVLASPAAAW 16 15ASPAAAWKCL 16 62 EEAGATAEAQ 16 132 WEFLLRLLKS 16 20 AWKCLGANIL 15 5VILDLSVEVL 14 11 VEVLASPAAA 14 42 WQQDRKIPPL 14 51 LSTPPPPAMW 14 68AEAQESGIRN 14 71 QESGIRNKSS 14 102 DPPESPDRAL 14 113 AANSWRNPVL 14 127GVGPLWEFLL 14 151 AFTSWSLGEF 14 168 KLETIILSKL 14 29 LRGGLSEIVL 13 40IEWQQDRKIP 13 95 DEAQDSIDPP 13 108 DRALKAANSW 13 129 GPLWEFLLRL 13 130PLWEFLLRLL 13 141 SQAASGTLSL 13 158 GEFLGSGTWM 13 165 TWMKLETIIL 13 169LETIILSKLT 13 24 LGANILRGGL 12 27 NILRGGLSEI 12 33 LSEIVLPIEW 12 122LPHTNGVGPL 12 123 PHTNGVGPLW 12 126 NGVGPLWEFL 12 139 LKSQAASGTL 12 146GTLSLAFTSW 12 19 AAWKCLGANI 11 31 GGLSEIVLPI 11 61 TEEAGATAEA 11 66ATAEAQESGI 11 125 TNGVGPLWEF 11 148 LSLAFTSWSL 11 152 FTSWSLGEFL 11 157LGEFLGSGTW 11 160 FLGSGTWMKL 11 163 SGTWMKLETI 11 181 QKSKHCMFSL 11 182KSKHCMFSLI 11 39 PIEWQQDRKI 10 76 RNKSSSSSQI 9 83 SQIPVVGVVT 9 105ESPDRALKAA 9

TABLE XLIV V8-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 17; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 7 EEGMGGTIPH 14 6 LEEGMGGTIP 11 5FLEEGMGGTI 9 8 EGMGGTIPHV 7

TABLE XLIV V13-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 27; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 9 TFLPNGINGI 16 1 GSPKSLSETF 12 2SPKSLSETFL 11 6 LSETFLPNGI 11 7 SETFLPNGIN 11

TABLE XLIV V14-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 29; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 1 ENLPLRLFTF 18 2 NLPLRLFTFW 14 10FWRGPVVVAI 13

TABLE XLIV V21-HLA-B4402- 10mers-98P4B6 Each peptide is a portion of SEQID NO: 43; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 6 QEQKTKHCMF 20 9 KTKHCMFSLI 11 8QKTKHCMFSL 10

TABLE XLIV V25-HLA-B4402-10mers-98PB36 Each peptide is a portion of SEQID NO: 51; each start position is specified, the length of peptide is 10amino acids, and the end position for each peptide is the start positionplus nine. Pos 1234567890 score 3 LFLPCISQKL 15 6 PCISQKLKRI 14 10 QKLKRIKKGW 13 9 SQKLKRIKKG  8 2 ILFLPCISQK  7

TABLE XLV V1-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V2-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V5A-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V5B-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V6-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V7A-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V7B-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V7C-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V8-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V13-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V14-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V21-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLV V25-HLA-B5101-10mers-98P4B6 Pos 1234567890 scoreNoResultsFound.

TABLE XLVI V1-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 3; each start position is specified, the length of peptide is15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 143 VKGFNVVDSAWLQLG 33266 LLSLVYLAGLLAAAY 33 367 SLGLLSLLAVTSIPS 32 1 MESISMMGSPKSLSE 31 130AEYLASLFPDSLIVK 30 30 KVTVGVIGSGDFAKS 29 431 NFVLALVLPSIVILD 29 206LRLFTLWRGPVVVAI 28 215 PVVVAISLATFFFLY 28 370 LLSLLAVTSIPSVSN 28 438LPSIVILDLLQLCRY 28 101 LWDLRHLLVGKILID 27 185 LNFIPIDLGSLSSAR 27 356RIEMYISFGIMSLGL 27 360 YISFGIMSLGLLSLL 27 397 TLGYVALLISTFHVL 27 421EEYYRFYTPPNFVLA 27 38 SGDFAKSLTIRLIRC 26 102 WDLRHLLVGKILIDV 26 122INQYPESNAEYLASL 26 149 VSAWALQLGPKDASR 26 244 QSDFYKIPIEIVNKT 26 249KIPIEIVNKTLPIVA 26 256 NKTLPIVAITLLSLV 26 261 IVAITLLSLVYLAGL 26 298WLQCRKQLGLLSFFF 26 368 LGLLSLLAVTSIPSV 26 109 VGKILIDVSNNMRIN 25 137FPDSLIVKGFNVVSA 25 145 GFNVVSAWALQLGPK 25 198 AREIENLPLRLFTLW 25 222LATFFFLYSFVRDVI 25 252 IEIVNKTLPIVAITL 25 264 ITLLSLVYLAGLLAA 25 302RKQLGLLSFFFAMVH 25 309 SFFFAMVHVAYSLCL 25 354 VWRIEMYISFGIMSL 25 362SFGIMSLGLLSLLAV 25 365 IMSLGLLSLLAVTSI 25 51 RCGYHVVIGSRNPKF 24 98YTSLWDLRHLLVGKI 24 106 HLLVGKILIDVSNNM 24 150 SAWALQLGPKDASRQ 24 184QLNFIPIDLGSLSSA 24 205 PLRLFTLWRGPVVVA 24 229 YSFVRDVIHPYARNQ 24 269LVYLAGLLAAAYQLY 24 330 RYLFLNMAYQQVHAN 24 335 NMAYQQVHANIENSW 24 388WREFSFIQSTLGYVA 24 391 FSFIQSTLGYVALLI 24 398 LGYVALLISTFHVLI 24 427YTPPNFVLALVLPSI 24 430 PNFVLALVLPSIVIL 24 52 CGYHVVIGSRNPKFA 23 55HVVIGSRNPKFASEF 23 186 NFIPIDLGSLSSARE 23 214 GPVVVAISLATFFFL 23 258TLPIVAITLLSLVYL 23 351 EEEVWRIEMYISFGI 23 352 EEVWRIEMYISFGIM 23 127ESNAEYLASLFPDSL 22 178 VIELARQLNFIPIDL 22 189 PIDLGSLSSAREIEN 22 211LWRGPVVVAISLATF 22 216 VVVAISLATFFFLYS 22 255 VNKTLPIVAITLLSL 22 301CRKQLGLLSFFFAMV 22 312 FAMVHVAYSLCLPMR 22 359 MYISFGIMSLGLLSL 22 364GIMSLGLLSLLAVTS 22 395 QSTLGYVALLISTFH 22 432 FVLALVLPSIVILDL 22 435ALVLPSIVILDLLQL 22 20 NGINGIKDARKVTVG 21 117 SNNMRINQYPESNAE 21 161ASRQVYICSNNIQAR 21 174 ARQQVIELARQLNFI 21 277 AAAYQLYYGTKYRRF 21 373LLAVTSIPSVSNALN 21 399 GYVALLISTFHVLIY 21 407 TFHVLIYGWKRAFEE 21 31VTVGVIGSGDFAKSL 20 142 IVKGFNVVSAWALQL 20 209 FTLWRGPVVVAISLA 20 346ENSWNEEEVWRIEMY 20 385 ALNWREFSFIQSTLG 20 429 PPNFVLALVLPSIVI 20 45LTIRLIRCGYHVVIG 19 80 EDALTKTNIIFVAIH 19 95 REHYTSLWDLRHLLV 19 135SLFPDSLIVKGFNVV 19 139 DSLIVKGFNVVSAWA 19 224 TFFFLYSFVRDVIHP 19 259LPIVAITLLSLVYLA 19 280 YQLYYGTKYRRFPPW 19 281 QLYYGTKYRRFPPWL 19 288YRRFPPWLETWLQCR 19 307 LLSFFFAMVHVAYSL 19 322 CLPMRRSERYLFLNM 19 328SERYLFLNMAYQQVH 19 357 IEMYISGFIMSLGLL 19 400 YVALLISTFHVLIYG 19 424YRFYTPPNFVLALVL 19 7 MGSPKSLSETCLPNG 18 25 IKDARKVTVGVIVSG 18 27DARKVTVGVIGSGDF 18 39 GDFAKSLTIRLIRCG 18 47 IRLIRCGYHVVIGSR 18 62NPKFASEFFPHVVDV 18 129 NAEYLASLFPDSLIV 18 163 RQYVICSNNIQARQQ 18 167ICSNNIQARQQVIEL 18 179 IELARQLNFIPIDLG 18 190 IDLGSLSSAREIENL 18 236IHPYARNQQSDFYKI 18 267 LSLVYLAGLLAAAYQ 18 268 SLVYLAGLLAAAYQL 18 285GTKYRRFPPWLETWL 18 296 ETWLQCRKQLGLLSF 18 299 LQCRKQLGLLSFFFA 18 326RRSERYLFLNMAYQQ 18 380 PSVSNALNWERFSFI 18 383 SNALNWREFSFIQST 18 390EFSFIQSTLGYVALL 18 405 ISTFHVLIYGWKRAF 18 410 VLIYGWKRAFEEEYY 18 423YYRFYTPPNFVLALV 18 433 VLALVLPSIVILDLL 18 22 INGIKDARKVTVGVI 17 29RKVTVGVIGSGDFAK 17 33 VGVIGSGDFAKSLTI 17 34 GVIGSGDFAKSLTIR 17 44SLTIRLIRCGYHVVI 17 46 TIRLIRCGYHVVIGS 17 46 TIRLIRCGYHVVIGS 17 54YHVVIGSRNPKFASE 17 58 IGSRNPKFASEFFPG 17 77 THHEDALTKTNIIFV 17 87NIIFVAIHREHYTSL 17 90 FVAIHREHYTSLWDL 17 105 RHLLVGKILIDVSNN 17 119NMRINQYPESNAEYL 17 138 PDSLIVKGFNVVSAW 17 140 SLIVKGFNVVSAWAL 17 151AWALQLGPKDASRQV 17 154 LQLGPKDASRQVYIC 17 176 QQVIELARQLNFIPI 17 187FIPIDLGSLSSAREI 17 195 LSSAREIENLPLRLF 17 217 VVAISLATFFFLYSF 17 226FFLYSFVRDVIHPYA 17 232 VRDVIHPYARNQQSD 17 251 PIEIVNKTLPIVAIT 17 253EIVNKTLPIVAITLL 17 270 VYLAGLLAAAYQLYY 17 271 YLAGLLAAAYQLYYG 17 305LGLLSFFFAMVHVAY 17 316 HVAYSLVLPMRRSER 17 317 VAYSLCLPMRRSERY 17 329ERYLFLNMAYQQVHA 17 361 ISFGIMSLGLLSLLA 17 363 FGIMSLGLLSLLAVT 17 389REFSFIQSTLGYVAL 17 392 SFIQSTLGYVALLIS 17 406 STFHVLIYGWKRAFE 17 408FHVLIYGWKRAFEEE 17 436 LVLPSIVILDLLQLC 17 2 ESISMMGSPKSLSET 16 3SISMMGSPKSLSETC 16 8 GSPKSLSETCLPNGI 16 11 KSLSETCLPNGINGI 16 16TCLPNGINGIKDARK 16 24 GIKDARKVTVGVIGS 16 59 GSRNPKFASEFFPHV 16 67SEFFPHVVDVTHHED 16 71 PHVVDVTHHEDALTK 16 103 DLRHLLVGKILIDVS 16 111KILIDVSNNMRINQY 16 126 PESNAEYLASLGPDS 16 153 ALQLGPKDASRQVYI 16 166YICSNNIQARQQVIE 16 171 NIQARQQVIELARQL 16 175 RQQVIELARQLNFIP 16 182ARQLNFIPIDLGSLS 16 200 EIENLPLRLFTLWRG 16 208 LFTLWRGPVVVAISL 16 219AISLATFFFLYSFVR 16 225 FFFLYSFVRDVIHPY 16 263 AITLLSLVYLAGLLA 16 265TLLSLVYLAGLLAAA 16 294 WLETWLQCRKQLGLL 16 304 QLGLLSFFFAMVHVA 16 308LSFFFAMVHVAYSLC 16 310 FFFAMVHVAYSLCLP 16 314 MVHVAYSLCLPMRRS 16 371LSLLAVTSIPSVSNA 16 394 IQSTLGYVALLISTF 16 401 VALLISTFHVLIYGW 16 420EEEYYRFYTPPNFVL 16 428 TPPNFVLALVLPSIV 16 440 SIVILDLLQLCRYPD 16

TABLE XLVI V2-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 5, each start position is specified, the length of peptide is15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 17 FTPFSCLSLPSSWDY 2628 SWDYRCPPPCPADFF 26 6 LQALSLSLSSGFTPF 25 8 ALSLSLSSGFTPFSC 25 3SPGLQALSLSLSSGF 24 10 SLSLSSGFTPFSCLS 22 14 SSGFTPFSCLSLPSS 19 26PSSWDYRCPPPCPAD 16 31 YRCPPPCPADFFLYF 16 1 SGSPGLQALSLSLSS 15 4PGLQALSLSLSSGFT 15 20 FSCLSLPSSWDYRCP 15 2 GSPGLQALSLSLSSG 14 7QALSLSLSSGFTPFS 14 13 LSSGFTPFSCLSLPS 14 16 GFTPFSCLSLPSSWD 14 19PFSGLSLPSSWDYRC 14 27 SSWDYRCPPPCPADF 14 30 DYRCPPPCPADFFLY 14

TABLE XLVI V5A-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 11 LRLFTFWRPGVVVAI 283 AREIENLPLRLFTFW 25 16 FWRGPVVVAISLATF 22 14 FTFWRGPVVVAISLA 20 13LFTFWRGPVVVAISL 18 5 EIENLPLRLFTFWRG 16 10 PLRLFTFWRGPVVVA 16 12RLFTFWRGPVVVAIS 15 2 SAREIENLPLRLFTF 14 7 ENLPLRLFTFWRGPV 14 15TFWRGPVVVAISLAT 14

TABLE XLVI V5B-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 7 WREFSFIQIFCSFAD 25 9EFSFIQIFCSFADTQ 24 4 ALNWREFSFIQIFCS 20 2 SNALNWREFSFIQLF 18 20ADTQTELELEFVFLL 18 8 REFSFIQIFCSFADT 17 10 FSFIQIFCSFADTQT 17 22TQTELELEFVFLLTL 17 23 QTELELEFVFLLTLL 17 12 FIQIFCSFADTQTEL 16 16FCSFADTQTELELEF 16 17 GSFADTQTELELEFV 14

TABLE XLVI V6-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 13; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 1 NFVLALVLPSIVILG 29 8LPSIVILGKJILFLP 29 46 GGTLPHVSPERVTVM 28 17 IILFLPCISRKLKRI 26 11IVILGKIILFLPCIS 24 38 SQFLEEGIGGTIPHV 24 39 QFLEEGIGGTIPHVS 24 7VLPSIVILGKIILFL 23 14 LGKIILFLPCISRKL 23 2 FVLALVLPSIVILGK 22 42EEGIGGTIPHVSPER 22 13 ILGKIILFLPCISRK 19 3 VLALVLPSIVILGKI 18 6LVLPSIVILGKIILF 18 9 PSIVILGKIILFLPC 17 15 GKIILFLPCISRKLK 17 5ALVLPSIVILGKIIL 16 10 SIVILGKIILFLPCI 16 18 ILFLPCISRKLKRIK 15 25SRKLKRIKKGWEKSQ 15 30 RIKKGWEKSQFLEEG 14 43 EGIGGTIPHVSPERV 14

TABLE XLVI V7A-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 12 SETFLPNGINGIKDA 215 MGSPKSLSETFLPNG 18 1 SISMMGSPKSLSETF 16 4 MMGSPKSLSETFLPN 16 6GSPKSLSETFLPNGI 16 9 KSLSETFLPNGINGI 16 14 TFLPNGINGIKDARK 16 2ISMMGSPKSLSETFL 14 15 FLPNGINGIKDARKV 13 10 SLSETFLPNGINGIK 10

TABLE XLVI V7B-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis the start position plus fourteen. Pos 123456789012345 score 4RYLFLNMAYQQSTLG 24 14 QSTLGYVALLISTFH 22 7 FLNMAYQQSTLGYVA 21 2SERYLFLNMAYQQST 19 9 NMAYQQSTLGYVALL 18 3 ERYLFLNMAYQQSTL 17 11AYQQSTLGYVALLIS 17 10 MAYQQSTLGYVALLI 16 13 QQSTLGYVALLISTF 16 8LNMAYQQSTLGYVAL 14

TABLE XLVI V7C-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 23 AAAWKCLGANILRGG 36168 SGTWMKLETIILSKL 35 138 EFLLRLLKSQAASGT 33 13 DLSVEVLASPAAAWK 30 50DRKIPPLSTPPPPAM 30 28 CLGANILRGGLSEIV 28 62 PAMWTEEAGATAWAQ 27 110ESPDRALKAANSWRN 26 124 NPVLPHTNGVGPLWE 26 141 LRLLKSQAASGTLSL 25 8SIVILDLSVEVLASP 24 31 ANILRGGLSEIVLPI 24 42 VLPIEWQQDRKIPPL 24 77ESGIRNKSSSSSQIP 24 130 TNGVGPLWEFLLRLL 24 137 WEFLLRLLKSQAASG 24 7PSIVILDLSVEVLAS 23 12 LDLSVEVLASPAAAW 23 150 SGTLSLAFTSWSLGE 23 171WMKLETIILSKLTQE 23 3 ALVLPSIVILDLSVE 22 53 IPPSLTPPPPAMWTE 22 157FTSWSLGEFLGSGTW 22 89 QIPVVGVVTEDDEAQ 21 6 LPSIVILDLSVEVLA 20 58TPPPPAMWTEEAGAT 20 97 TEDDEAQDSIDPPES 20 100 DEAQDSIDPPESPDR 20 134GLPWEFLLRLLKSQA 19 154 SLAFTSWSLGEFLGS 19 1 VLALVLPSIVILDLS 18 22PAAAWKCLGANILRG 18 44 PIEWQQDRKIPPLST 18 122 WRNPBLPHTNGVGPL 18 135PLWEFLLRLLKSQAA 18 140 LLRLLKSQAASGTLS 18 148 AASGTLSLAFTSWSL 18 159SWSLGEFLGSGTWMK 18 161 SLGEFLGSGTWNKLE 18 169 GTWMKLETIILSKLT 18 176TIILSKLTQEQKSKH 18 4 LVLPSIVILDLSVEV 17 9 IVILDLSVEVLASPA 17 30GANILRGGLSEIVLP 17 61 PPAMWTEEAGATAEA 17 67 EEAGATAEAQESGIR 17 94GVVTEDDEAQDSIDP 17 101 EAQDSIDPPESPDRA 17 107 DPPESPDRALKAANS 17 133VGPLWEFLLRLLKSQ 17 143 LLKSQAASGTLSLAF 17 162 LGEFLGSGTQMKLET 17 163GEFLGSGTWMKLETI 17 172 MKLETIILSKLTQEQ 17

TABLE XLVI V8-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 17; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 8 SQFLEEGMGGTIPHV 24 9QFLEEGMGGTIPHVS 24 12 EEGMGGTIPHVSPER 22 13 EGMGGTIPHVSPERV 14 7KSQFLEEGMGGTIPH 13 2 KKGWEKSQFLEEGMG 12 6 EKSQFLEEGMGGTIP 12

TABLE XLVI V13-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 27; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 12 SETFLPNGINGIKDA 215 MGSPKSLSETFLPNG 18 1 SISMMGSPKSLSETF 16 4 MMGSPKSLSETFLPN 16 6GSPKSLSETFLPNGI 16 9 KSLSETFLPNGINGI 16 14 TFLPNGINGIKDARK 16 2ISMMGSPKSLSETFL 14 15 FLPNGINGIKDARKV 13 10 SLSETFLPNGINGIK 10

TABLE XLVI V14-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 29; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 10 LRLFTFWRGPVVVAI 282 AREIENLPLRLFTFW 25 15 FWRGPVVVAISLATF 22 13 FTFWRGPVVVAISLA 20 12LFTFWRGPVVVAISL 18 4 EIENLPLRLFTFWRG 16 9 PLRLFTFWRGPVVVA 16 11RLFTFWRGPVVVAIS 15 1 SAREIENLPLRLFTF 14 6 ENLPLRLFTFWRGPV 14 14TFWRGPVVVAISLAT 14 8 LPLRLFTFWRGPVVV 12

TABLE XLVI V21-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 43; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 3 TIILSKLTQEQKTKH 18 2ETIILSKLTQEQKTK 14 7 SKLTQEQKTKHCMFS 13 6 LSKLTQEQKTKHCMF 11 11QEQKTKHCMFSLISG 11 1 LETIILSKLTQEQKT 10 9 LTQEQKTKHCMFSLI 10 10TQEQKTKHCMFSLIS 9 12 EQKTKHCMFSLISGS 9 5 ILSKLTQEQKTKHCM 8 8KLTQEQKTKHCMFSL 8

TABLE XLVI V25-HLA-DRB1-0101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 51; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 6 IILFLPCISQKLKRI 25 3LGKIILFLPCISQKL 23 2 ILGKIILFLPCISQK 19 4 GKIILFLPCISQKLK 17 7ILFLPCISQKLKRIK 15 9 FLPCISQKLKRIKKG 15 14 SQKLKRIKKGWEKSQ 15 15QKLKRIKKGWEKSQF 13

TABLE XLVII V1-HLA-DRB1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 3; each start position is specified, the length of peptide is15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 97 HYTSLWDLRHLLVGK 28176 QQVIELARQLNFIPI 27 228 LYSFVRDVIHPYARN 27 322 CLPMRRSERYLFLNM 27 54YHVVIGSRNPKFASE 26 296 ETWLQCRKQLGLLSF 26 408 FHVLITGWKRAFEEE 26 273AGLLAAAYQLYYGTK 25 439 PSIVILDLLQLCRYP 25 109 VGKILIDVSNNMRIN 24 288YRRFPPWLETWLQCR 24 87 NIIFVAIHREHYTSL 23 423 YYRFYTPPNFVLALV 23 133LASLFPDSLIVKGFN 22 185 LNFIPIDLGSLSSAR 22 261 IVAITLLSLVYLAGL 22 272LAGLLAAAYQLYYGT 22 433 VLALVLPSIVILDLL 22 145 GFNVVSAWALQLGPK 21 214GPVVVAISLATFFFL 21 269 LVYLAGLLAAAYQLY 21 362 SFGIMSLGLLSLLAV 21 363FGIMSLGLLSLLAVT 21 175 RQQVIELARQLNFIP 20 198 AREIENLPLRLFTLW 20 258TLPIVAITLLSLVYL 20 264 ITLLSLVYLAGLLAA 20 376 VTSIPSVSNALNWRE 20 400YVALLISTFHVLIYG 20 435 ALVLPSIVILDLLQL 20 438 LPSIVILDLLQLCRY 20 440SIVILDLLQLCRYPD 20 30 KVTVGVIGSGDFAKS 19 53 GYHVVIGSFNPKFAS 19 110GKILIDVSNNMRINQ 19 130 AEYLASLFPDSLIVK 19 151 AWALQLGPKDASRQV 19 215PVVVAISLATFFFLY 19 217 VVAISLATFFFLYSF 19 256 NKTLPIVAITLLSLV 19 312FAMVHVAYSLVLPMR 19 320 SLCLPMRRSERYLFL 19 402 ALLISTFHVLIYGWK 19 3SISMMGSPKSLSETC 18 22 INGIKDARKVTVGVI 18 34 GVIGSGDFAKSLTIR 18 90FVAIHREHYTSLWDL 18 119 NMRINQYPESNAEYL 18 139 DSLIVKGFNVVSAWA 18 143VKGFNVVSAWALQLG 18 162 SRQVYICSNNIQARQ 18 184 QLNFIPIFLGSLSSA 18 195LSSAREIENLPLRLF 18 233 RDVIHOYARNQQSDF 18 308 LSFFFAMVHVAYSLC 18 331YLFLNMAYQQVHANI 18 360 YISFGIMSLGLLSLL 18 409 HVLIYGWKRAFEEEY 18 7MGSPKSLSETCLPNG 17 21 GINGIKDARKVTVGV 17 38 SGDFAKSLTIRLIRC 17 113LIDVSNNMRINQYPE 17 121 RINQYPESNAEYLAS 17 155 QLGPKDASRQVYICS 17 169SNNIQARQQVIELAR 17 178 VIELARQLNFIPIDL 17 192 LGSLSSAREIENLPL 17 225FFFLYSFVRDVIHPY 17 249 KIPIEIVNKTLPIVA 17 292 PPWLETWLQCRKQLG 17 318AYSLCLPMRRSERYL 17 327 RSERYLFLNMATQQV 17 338 YQQHVANIENSWNEE 17 379IPSVSNALNWREFSF 17 416 KRAFEEEYYRFYTPP 17 15 ETCLPNGINGIKDAR 16 72HVVDVTHHEDALTKT 16 79 HEDALTKTNIIFVAI 16 88 IIFVAIHREHYTSLW 16 111KILIDVSNNMRINQY 16 205 PLRLFTLWRGPVVVA 16 248 YKIPIEIVNKTLPIV 16 279AYQLYYGTKYRRFPP 16 342 HANIENSWNEEEVWR 16 382 VSNALNWREFSFIQS 16 413YGWKRAFEEEYYRFY 16 43 KSLTIRLIRCGYHVV 15 263 AITLLSLVYLAGLLA 15 294WLETWLQCRKQLGLL 15 321 LCLPMRRSERYLFLN 15 367 SLGLLSLLAVTSIPS 15 387NWREFSFIQSTLGYV 15 412 IYGWKRAFEEEYYRF 15 73 VVDVTHHEDALTKTN 14 104LRHLLVGKILIDVSN 14 236 IHPYARNQQSDFYKI 14 267 LSLVYLAGLLAAAYQ 14 304QLGLLSFFFAMVHVA 14 365 IMSLGLLSLLAVTSI 14 373 LLAVTSIPSVSNALN 14 401VALLISTFHVLIYGW 14 434 LALVLPSIVILDLLQ 14 1 MESISMMGSPKSLSE 13 4ISMMGSPKSLSETCL 13 32 TVGVIGSGDFAKSLT 13 33 VGVIGSGDFAKSLTI 13 101LWDLRHLLVGKILID 13 138 PDSLIVKGFNVVSAW 13 164 QVYICSNNIQARQQV 13 189PIDLGSLSSAREIEN 13 201 IENLPLRLFTLWRGP 13 213 RGPVVVAISLATFFF 13 266LLSLVYLAGLLAAAY 13 407 TFHVLITGWKRAFEE 13

TABLE XLVII V2-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 5; each start position is specified, the length of peptide is15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 6 LQALSLSLSSGFTPF 2014 SSGFTPFSCLSLPSS 20 20 FSCLSLPSSWDYRCP 20 24 SLPSSWDYRCPPPCP 16 2GSPGLQALSLSLSSG 12 3 SPGLQALSLSLSSGF 12 8 ALSLSLSSGFTPFSC 12 9LSLSLSSGFTPFSCL 12 10 SLSLSSGFTPFSCLS 11 22 CLSLPSSWDYRCPPP 11 30DYRCPPPCPADFFLY 10 31 YRCPPPCPADFFLYF 10 12 SLSSGFTPFSCLSLP 9 17FTPFSCLSLPSSWDY 9

TABLE XLVII V5A-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 3 AREIENLPLRLFTFW 2010 PLRLFTFWRGPVVVA 16 2 SAREIENLPLRLFTF 12 6 IENLPLRLFTFWRGP 12 8NLPLRLFTFWRGPVV 12 5 EIENLPLRLFTFWRG 11 13 LFTFWRGPVVVAISL 10 4REIENLPLRLFTFWR 9 11 LRLFTFWRGPVVVAI 9

TABLE XLVII V5B-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 15 IFCSFADTQTELELE 2423 QTELELEFVFLLTLL 20 1 VSNALNWREFSFIQI 16 19 FADTQTELELEFVFL 16 21DTQTELELEFVFLLT 16 17 CSFADTQTELELEFV 15 22 TQTELELEFVFLLTL 13 2SNALNWREFSFIQIF 11 10 FSFIQIFCSFADTQT 11

TABLE XLVII V6-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID No: 13; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 8 LPSIVILGKIILFLP 26 3VLALVLPSIVILGKI 22 9 PSIVILGKIILFLPC 22 10 SIVILGKIILFLPCI 21 17IILFLPCISRKLKRI 20 18 ILFLPCISRKLKRIK 18 25 SRKLKRIKKGWEKSQ 18 21LPCISRKLKRIKKGW 17 28 LKRIKKGWEKSQFLE 17 29 KRIKKGWEKSQFLEE 16 4LALVLPSIVILGKII 14 14 LGKIILFLPCISRKL 13 15 GKIILFLPCISRKLK 13 1NFVLALVLPSIVILG 12 5 ALVLPSIVILGKIIL 12 37 KSQFLEEGIGGTIPH 12

TABLE XLVII V7A-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 1 SISMMGSPKSLSETF 18 5MGSPKSLSETFLPNG 17 13 ETFLPNGINGIKDAR 16 2 ISMMGSPKSLSETFL 13 12SETFLPNGINGIKDA 13 8 PKSLSETFLPNGING 12 4 MMGSPKSLSETFLPN 9 10SLSETFLPNGINGIK 8

TABLE XLVII V7B-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 5 YLFLNMAYQQSTLGY 18 1RSERYLFLNMAYQQS 17 6 LFLNMAYQQSTLGYV 14 12 YQQSTLGYVALLIST 12 3ERYLFLNMAYQQSTL 11 4 RYLFLNMAYQQSTLG 11 7 FLNMAYQQSTLGYVA 11 11AYQQSTLGYVALLIS 11 14 QSTLGYVALLISTFH 11 8 LNMAYQQSTLGYVAL 10

TABLE XLVII V7C-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 93 VGVVTEDDEAQDSID 29130 TNGVGPLWEFLLRLL 26 7 PSIVILDLSVEVLAS 24 1 VLALVLPSIVILDLS 22 8SIVILDLSVEVLASP 21 133 VGPLWEFLLRLLKSQ 21 3 ALVLPSIVILDLSVE 20 163GEFLGSGTWMKLETI 20 9 IVILDLSVEVLASPA 19 123 RNPVLPHTNGVGPLW 19 137WEFLLRLLKSQAASG 19 154 SLAFTSWSLGEFLGS 19 171 WMKLETIILSKLTQE 19 38LSEIVLPIEWQQDRK 18 179 LSKLTQEQKSKHCMF 18 40 EIVLPIEWQQDRKIP 17 44PIEWQQDRKIPPLST 16 90 IPVVGVVTEDDEAQD 16 176 TIILSKLTQEQKSKH 16 15SVEVLASPAAAWKCL 15 27 KCLGANILRGGLSEI 15 32 NILRGGLSEIVLPIE 15 39SEIVLPIEWQQDRKI 15 116 LKAANSWRNPVLPHT 15 138 EFLLRLLKSQAASGT 15 175ETIILSKLTQEQKSK 15 2 LALVLPSIVILDLSV 14

TABLE XLVII V8-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 17; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 7 KSQFLEEGMGGTIPH 12 8SQFLEEGMGGTIPHV 11 12 EEGMGGTIPHVSPER 10 1 TKKGWEKSQFLEEGM 9 4GWEKSQFLEEGMGGT 7 5 WEKSQFLEEGMGGTI 7

TABLE XLVII V13-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 27; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 1 SISMMGSPKSLSETF 18 5MGSPKSLSETFLPNG 17 13 ETFLPNGINGIKDAR 16 2 ISMMGSPKSLSETFL 13 12SETFLPNGINGIKDA 13 8 PKSLSETFLPNGING 12 4 MMGSPKSLSETFLPN 9 10SLSETFLPNG1NGIK 8

TABLE XLVII V14-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 29; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 2 AREIENLPLRLFTFW 20 9PLRLFTFWRGPVVVA 16 1 SAREIENLPLRLFTF 12 5 IENLPLRLFTFWRGP 12 7NLPLRLFTFWRGPVV 12 4 EIENLPLRLFTFWRG 11 12 LFTFWRGPVVVAISL 10 3REIENLPLRLFTFWR 9 10 LRLFTFWRGPVVVAI 9

TABLE XLVII V21-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 43; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 6 LSKLTQEQKTKHCMF 18 3TIILSKLTQEQKTKH 16 2 ETIILSKLTQEQKTK 15 1 LETIILSKLTQEQKT 13 4IILSKLTQEQKTKHC 10 5 ILSKLTQEQKTKHCM 9 9 LTQEQKTKHCMFSLI 9 11QEQKTKHCMFSLISG 9

TABLE XLVII V25-HLA-DR1-0301-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 51; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 6 IILFLPCISQKLKRI 21 7ILFLPCISQKLKRIK 18 14 SQKLKRIKKGWEKSQ 18 10 LPCISQKLKRIKKGW 17 3LGKIILFLPCISQKL 13 4 GKIILFLPCISQKLK 13 5 KIILFLPCISQKLKR 11

TABLE XLVIII V1-HLA-DR1-0401-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 3; each start position is specified, the length of peptide is15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 420 EEEYYRFYTPPNFVL 2898 YTSLWDLRHLLVGKI 26 109 VGKILIDVSNNMRIN 26 175 RQQVIELARQLNFIP 26 205PLRLFTLWRGPVVVA 26 213 RGPVVVAISLATFFF 26 225 FFFLYSFVRDVIHPY 26 229YSFVRDVIHPYARNQ 26 312 FAMVHVAYSLCLPMR 26 370 LLSLLAVTSIPSVSN 26 373LLAVTSIPSVSNALN 26 376 VTSIPSVSNALNWRE 26 38 SGDFAKSLTIRLIRC 22 51RCGYHVVIGSRNPKF 22 62 NPKFASEFFPHVVDV 22 87 NIIFVAIHREHYTSL 22 143VKGFNVVSAWALQLG 22 163 RQVYICSNNIQARQQ 22 184 QLNFIPIDLGSLSSA 22 222LATFFFLYSFVRDVI 22 244 QSDFYKIPIEIVNKT 22 307 LLSFFFAMVHVAYSL 22 309SFFFAMVHVAYSLCL 22 328 SERYLFLNMAYQQVH 22 346 ENSWNEEEVWRIEMY 22 357IEMYISFGIMSLGLL 22 385 ALNWREFSFIQSTLG 22 388 WREFSFIQSTLGYVA 22 405ISTFHVLIYGWKRAF 22 423 YYRFYTPPNFVLALV 22 429 PPNFVLALVLPSIVI 22 1MESISMMGSPKSLSE 20 15 ETCLPNGINGIKDAR 20 19 PNGINGIKDARKVTV 20 22INGIKDARKVTVGVI 20 30 KVTVGVIGSGDFAKS 20 47 IRLIRCGYHVVIGSR 20 53GYHVVIGSRNPKFAS 20 70 FPHVVDVTHHEDALT 20 71 PHVVDVTHHEDALTK 20 86TNILFVATHREHYTS 20 90 FVAIHREHYTSLWDL 20 101 LWDLRHLLVGKILID 20 106HLLVGKILIDVSNNM 20 110 GKILIDVSNNMRINQ 20 111 KILIDVSNNMRINQY 20 113LIDVSNNMRINQYPE 20 130 AEYLASLFPDSLIVK 20 133 LASLFPDSLIVKGFN 20 139DSLIVKGFNVVSAWA 20 140 SLIVKGFNVVSAWAL 20 145 GFNVVSAWALQLGPK 20 162SRQVYICSNNIQARQ 20 176 QQVIELARQLNFIPI 20 185 LNFIPIDLGSLSSAR 20 189PIDLGSLSSAREIEN 20 192 LGSLSSAREIENLPL 20 217 VVAISLATFFFLYSF 20 219AISLATFFFLYSFVR 20 233 RDVIHPYARNQQSDF 20 247 FYKIPIEIVNKTLPI 20 256NKTLPIVAITLLSLV 20 258 TLPIVAITLLSLVYL 20 261 IVAITLLSLVYLAGL 20 264ITLLSLVYLAGLLAA 20 266 LLSLVYLAGLLAAAY 20 267 LSLVYLAGLLAAAYQ 20 273AGLLAAAYQLYYGTK 20 292 PPWLETWLQCRKQLG 20 302 RKQLGLLSFFFAMVH 20 304QLGLLSFFFAMVHVA 20 331 YLFLNMAYQQVHANI 20 351 EEEVWRIEMYISFGI 20 354VWRIEMYISFGIMSL 20 362 SFGIMSLGLLSLLAV 20 365 IMSLGLLSLLAVTSI 20 367SLGLLSLLAVTSIPS 20 368 LGLLSLLAVTSIPSV 20 379 IPSVSNALNWREFSF 20 395QSTLGYVALLISTFH 20 398 LGYVALLISTFHVLI 20 401 VALLISTFHVLIYGW 20 430PNFVLALVLPSIVIL 20 431 NFVLALVLPSIVILD 20 435 ALVLPSIVILDLLQL 20 438LPSIVILDLLQLCRY 20 440 SIVTLDLLQLCRYPD 20 12 SLSETCLPNGINGIK 18 21G1NGIKDARKVTVGV 18 36 IGSGDFAKSLTIRLI 18 76 VTHHEDALTKTNIIF 18 97HYTSLWDLRHLLVGK 18 142 IVKGFNVVSAWALQL 18 154 LQLGPKDASRQVYIC 18 161ASRQVYICSNNIQAR 18 168 CSNNIQARQQVIELA 18 186 NFIPIDLGSLSSARE 18 195LSSAREIENLPLRLF 18 234 DVIHPYARNQQSDFY 18 248 YKIPIEIVNKTLPIV 18 257KTLPIVAITLLSLVY 18 289 RRFPPWLETWLQCRK 18 339 QQVHANIENSWNEEE 18 348SWNEEEVWRIEMYIS 18 359 MYISFGIMSLGLLSL 18 364 GIMSLGLLSLLAVTS 18 384NALNWREFSFIQSTL 18 387 NWREFSFIQSTLGYV 18 399 GYVALLISTFHVLIY 18 432FVLALVLPSIVILDL 18 66 ASEFFPHVVDVTHHE 16 67 SEFFPHVVDVTHHED 16 95REHYTSLWDLRHLLV 16 122 INQYPESNAEYLASL 16 129 NAEYLASLFPDSLIV 16 206LRLFTLWRGPVVVAI 16 209 FTLWRGPVVVAISLA 16 224 TFFFLYSFVRDVIHP 16 226FFLYSFVRDVIHPYA 16 228 LYSFVRDVIHPYARN 16 236 IHPYARNQQSDFYKI 16 245SDFYKIPIEIVNKTL 16 268 SLVYLAGLLAAAYQL 16 285 GTKYRRFPPWLETWL 16 288YRRFPPWLETWLQCR 16 308 LSFFFAMVHVAYSLC 16 330 RYLFLNMAYQQVHAN 16 335NMAYQQVHANIENSW 16 352 EEVWRIEMYISFGIM 16 360 YISFGIMSLGLLSLL 16 390EFSFIQSTLGYVALL 16 397 TLGYVALLISTFHVL 16 412 IYGWKRAFEEEYYRF 16 416KRAFEEEYYRFYTPP 16 424 YRFYTPPNFVLALVL 16 296 ETWLQCRKQLGLLSF 15 3SISMMGSPKSLSETC 14 4 ISMMGSPKSLSETCL 14 32 TVGVIGSGDFAKSLT 14 33VGVIGSGDFAKSLTI 14 44 SLTIRLIRCGYHVVI 14 46 TIRLIRCGYHVVIGS 14 54YHVVIGSRNPKFASE 14 73 VVDVTHHEDALTKTN 14 80 EDALTKTNIIFVAIH 14 85KTNIIFVAIHREHYT 14 88 IIFVAIHREHYTSLW 14 117 SNNMRINQYPESNAE 14 119NMRINQYPESNAEYL 14 151 AWALQLGPKDASRQV 14 178 VIELARQLNFIPIDL 14 182ARQLNFIPIDLGSLS 14 187 FIPIDLGSLSSAREI 14 198 AREIENLPLRLFTLW 14 203NLPLRLFTLWRGPVV 14 208 LFTLWRGPVVVAISL 14 214 GPVVVAISLATFFFL 14 232VRDVIHPYARNQQSD 14 249 KIPIEIVNKTLPIVA 14 252 IEIVNKTLPIVAITL 14 259LPIVAITLLSLVYLA 14 263 AITLLSLVYLAGLLA 14 269 LVYLAGLLAAAYQLY 14 272LAGLLAAAYQLYYGT 14 305 LGLLSFFFAMVHVAY 14 311 FFAMVHVAYSLCLPM 14 314MVHVAYSLCLPMRRS 14 318 AYSLCLPMRRSERYL 14 322 CLPMRRSERYLFLNM 14 329ERYLFLNMAYQQVHA 14 333 FLNMAYQQVHANIEN 14 342 HANIENSWNEEEVWR 14 356RIEMYISFGIMSLGL 14 363 FGIMSLGLLSLLAVT 14 371 LSLLAVTSIPSVSNA 14 391FSFIQSTLGYVALLI 14 400 YVALLISTFHVLIYG 14 402 ALLISTFHVLIYGWK 14 407TFHVLIYGWKRAFEE 14 409 HVLIYGWKRAFEEEY 14 433 VLALVLPSIVILDLL 14 439PSIVILDLLQLCRYP 14

TABLE XLVIII V5A-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 11; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 14SSGFTPFSCLSLPSS 22 17 FTPFSCLSLPSSWDY 22 3 SPGLQALSLSLSSGF 20 10SLSLSSGFTPFSCLS 20 2 GSPGLQALSLSLSSG 18 7 QALSLSLSSGFTPFS 18 28SWDYRCPPPCPADFF 16 6 LQALSLSLSSGFTPF 14 20 FSCLSLPSSWDYRCP 14 4PGLQALSLSLSSGFT 12 13 LSSGFTPFSCLSLPS 12 16 GFTPFSCLSLPSSWD 12 19PFSCLSLPSSWDYRC 12 24 SLPSSWDYRCPPPCP 12

TABLE XLVIII V5B-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 11; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 4ALNWREFSFIQIFCS 22 7 WREFSFIQIECSFAD 22 9 EFSFIQIFGSFADTQ 22 13IQIFCSFADTQTELE 22 10 FSFIQIFCSFADTQT 20 23 QTELELEFVFLLTLL 20 3NALNWREFSFIQIFC 18 15 IFGSFADTQTELELE 18 16 FCSFADTQTELELEF 16 12FIQIFCSFADTQTEL 14 6 NWREFSFIQIFCSFA 12 14 QIFCSFADTQTELEL 12 20ADTQTELELEFVFLL 12 22 TQTELELEFVFLLTL 12 24 TELELEFVFLLTLLL 12

TABLE XLVIII V6-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 13; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 18 ILFLPCISRKLKRTK 2617 IILFLPCISRKLKRI 22 37 KSQFLEEGIGGTIPH 22 1 NFVLALVLPSIVILG 20 5ALVLPSIVILGKIIL 20 8 LPSIVILGKIILFLP 20 14 LGKIILFLPCISRKL 20 46GGTIPHVSPERVTVM 20 2 FVLALVLPSIVILGK 18 22 PCISRKLKRIKKGWE 18 30RIKXGWEKSQFLEEG 18 3 VLALVLPSIVILGKI 14 11 IVILGKIILFLPCIS 14 15GKIILFLPCISRKLK 14 16 KIILFLPCISRKLKR 14 25 SRKLKRIKKGWEKSQ 14 28LKRIKXGWEKSQFLE 14 38 SQFLEEGIGGTIPHV 14 42 EEGIGGTIPHVSPER 14 6LVLPSIVILGKIILF 12 7 VLPSIVILGKIILFL 12 13 ILGKIILFLPCISRK 12 34GWEKSQFLEEGIGGT 12 43 EGIGGTIPHVSPERV 12

TABLE XLVIII V7A-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 15; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 13ETFLPNGINGIKDAR 20 10 SLSETFLPNGINGIK 18 12 SETFLPNGINGIKDA 16 1SISMMGSPKSLSETF 14 2 ISMMGSPKSLSETFL 14 5 MGSPKSLSETFLPNG 12 7SPKSLSETFLPNGIN 12 9 KSLSETFLPNGINGI 12

TABLE XLVIII V7B-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 15; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 5YLFLNMAYQQSTLGY 26 2 SERYLFLNMAYQQST 22 14 QSTLGYVALLISTFH 20 4RYLFLNMAYQQSTLG 16 9 NMAYQQSTLGYVALL 16 3 ERYLFLNMAYQQSTL 14 7FLNMAYQQSTLGYVA 14 1 RSERYLFLNMAYQQS 12 6 LFLNMAYQQSTLGYV 12 11AYQQSTLGYVALLIS 12 15 STLGYVALLISTFHV 12

TABLE XLVIII V7C-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 15; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 134GPLWEFLLRLLKSQA 28 168 SGTWMKLETIILSKL 28 7 PSIVILDLSVEVLAS 26 13DLSVEVLASPAAAWK 26 113 DRALKAANSWRNPVL 26 138 EFLLRLLKSQAASGT 26 150SGTLSLAFTSWSLGE 26 176 TIILSKLTQEQKSKH 26 23 AAAWKCLGANILRGG 22 62PAMWTEEAGATAEAQ 22 162 LGEFLGSGTWMKLET 22 3 ALVLPSIVLLDLSVE 20 8SIVILDLSVEVLASP 20 31 ANILRGGLSEIVLPI 20 40 EIVLPIEWQQDRKIP 20 50DRKIPPLSTPPPPAM 20 61 PPAMWTEEAGATAEA 20 89 QIPVVGVVTEDDEAQ 20 92VVGVVTEDDEAQDSI 20 130 TNGVGPLWEFLLRLL 20 133 VGPLWEFLLRLLKSQ 20 137WEFLLRLLKSQAASG 20 159 SWSLGEFLGSGTWMK 20 169 GTWMKLETIILSKLT 20 171WMKLETIILSKLTQE 20 27 KCLGANILRGGLSEI 18 74 EAQESGIRNKSSSSS 18 95VVTEDDEAQDSIDPP 18 142 RLLKSQAASGTLSLA 18 151 GTLSLAFTSWSLGEF 18 172MKLETIILSKLTQEQ 18 44 PIEWQQDRKIPPLST 16 119 ANSWRNPVLPHTNGV 16 157FTSWSLGEFLGSGTW 16 77 ESGIRNKSSSSSQIP 15 175 ETIILSKLTQEQKSK 15 1VLALVLPSIVILDLS 14 6 LPSIVILDLSVEVLA 14 9 IVILDLSVEVLASPA 14 11ILDLSVEVLASPAAA 14 16 VEVLASPAAAWKCLG 14 30 GANILRGGLSEIVLP 14 35RGGLSEIVLPIEWQQ 14 38 LSEIVLPIEWQQDRK 14 39 SEIVLPIEWQQDRKI 14 42VLPIEWQQDRKIPPL 14 53 IPPLSTPPPPAMWTE 14 87 SSQIPVVGVVTEDDE 14 90IPVVGVVTEDDEAQD 14 93 VGVVTEDDEAQDSID 14 103 QDSIDPPESPDRALK 14 123RNPVLPHTNGVGPLW 14 141 LRLLKSQAASGTLSL 14 163 GEFLGSGTWMKLETI 14 179LSKLTQEQKSKHCMF 14

TABLE XLVIII V8-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 17; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 7 KSQFLEEGMGGTIPH 22 8SQFLEEGMGGTIPHV 14 12 EEGMGGTLPHVSPER 14 4 GWEKSQFLEEGMGGT 12 13EGMGGTIPHVSPERV 12 2 KKGWEKSQFLEEGMG 10

TABLE XLVIII V13-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 27; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 13ETFLPNGINGIKDAR 20 10 SLSETFLPNGINGIK 18 12 SETFLPNGINGIKDA 16 1SISMMGSPKSLSETF 14 2 ISMMGSPKSLSETFL 14 5 MGSPKSLSETFLPNG 12 7SPKSLSETFLPNGIN 12 9 KSLSETFLPNGINGI 12

TABLE XLVIII V14-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 29; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 9PLRLFTFWRGPVVVA 26 10 LRLFTFWRGPVVVAI 16 12 LFTFWRGPVVVAISL 16 13FTFWRGPVVVAISLA 16 2 AREIENLPLRLFTFW 14 7 NLPLRLFTFWRGPVV 14 3REIENLPLRLFTFWR 12 6 ENLPLRLFTFWRGPV 12 14 TFWRGPVVVAISLAT 12 15FWRGPVVVAISLATF 12

TABLE XLVIII V21-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 43; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 3TIILSKLTQEQKTKH 26 2 ETIILSKLTQEQKTK 15 6 LSKLTQEQKTKHCMF 14 5ILSKLTQEQKTKHCM 12

TABLE XLVIII V25-HLA-DRB1-0401-15mers-98P4B6 Each peptide is a portionof SEQ ID NO: 51; each start position is specified, the length ofpeptide is 15 amino acids, and the end position for each peptide is thestart position plus fourteen. Pos 123456789012345 score 7ILFLPCISQKLKRIK 26 6 IILFLPCISQKLKRI 22 3 LGKIILFLPCISQKL 20 4GKIILFLPCISQKLK 20 11 PCISQKLKRIKKGWE 18 5 KIILFLPCISQKLKR 14 14SQKLKRIKKGWEKSQ 14 2 ILGKIILFLPCISQK 12

TABLE XLIX V1-HLA-DRB1-1101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 3; each start position is specified, the length of peptide is15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 249 KIPIEIVNKTLPIVA 27308 LSFFFAMVHVAYSLC 27 229 YSFVRDVIHPYARNQ 26 281 QLYYGTKYRRFPPWL 25 295LETWLQCRKQLGLLS 25 87 NIIFVAIHREHYTSL 24 388 WREFSFIQSTLGYVA 23 309SFFFAMVHVAYSLCL 22 3 SISMMGSPKSLSETC 21 71 PHVVDVTHHEDALTK 21 98YTSLWDLRHLLVGKI 21 175 RQQVIELARQLNFIP 21 205 PLRLFTLWRGPVVVA 21 70FPHVVDVTHHEDALT 20 95 REHYTSLWDLRHLLV 20 151 AWALQLGPKDASRQV 20 263AITLLSLVYLAGLLA 20 1 MESISMMGSPKSLSE 19 51 RCGYHVVIGSRNPKF 19 106HLLVGKILIDVSNNM 19 182 ARQLNFIPIDLGSLS 19 266 LLSLVYLAGLLAAAY 19 351EEEVWRIEMYISFGI 19 395 QSTLGYVALLISTFH 19 424 YRFYTPPNFVLALVL 19 67SEFFPHVVDVTHHED 18 222 LATFFFLYSFVRDVI 18 302 RKQLGLLSFFFAMVH 18 307LLSFFFAMVHVAYSL 18 367 SLGLLSLLAVTSIPS 18 370 LLSLLAVTSIPSVSN 18 28ARKVTVGVIGSGDFA 17 86 TNIIFVAIHREHYTS 17 99 TSLWDLRHLLVGKIL 17 134ASLFPDSLIVKGFNV 17 143 VKGFNVVSAWALQLG 17 225 FFFLYSFVRDVIHPY 17 226FFLYSFVRDVIHPYA 17 244 QSDFYKIPIEIVNKT 17 335 NMAYQQVHANIENSW 17 360YISFGIMSLGLLSLL 17 405 ISTFHVLIYGWKRAF 17 129 NAEYLASLFPDSLIV 16 136LFPDSLIVKGFNVVS 16 163 RQVYICSNNIQARQQ 16 184 QLNFIPIDLGSLSSA 16 268SLVYLAGLLAAAYQL 16 279 AYQLYYGTKYRRFPP 16 282 LYYGTKYRRFPPWLE 16 328SERYLFLNMAYQQVH 16 330 RYLFLNMAYQQVHAN 16 385 ALNWREFSFIQSTLG 16 397TLGYVALLISTFHVL 16 429 PPNFVLALVLPSIVI 16 42 AKSLTIRLIRCGYHV 15 47IRLIRCGYHVVIGSR 15 103 DLRHLLVGKILIDVS 15 142 IVKGFNVVSAWALQL 15 210TLWRGPVVVAISLAT 15 317 VAYSLCLPMRRSERY 15 318 AYSLCLPMRRSERYL 15 322CLPMRRSERYLFLNM 15 401 VALLISTFHVLIYGW 15 408 FHVLIYGWKRAFEEE 15 428TPPNFVLALVLPSIV 15 19 PNGINGIKDARKVTV 14 22 INGIKDARKVTVGVI 14 43KSLTIRLIRCGYHVV 14 52 CGYHVVIGSRNPKFA 14 53 GYHVVIGSRNPKFAS 14 56VVIGSRNPKFASEFF 14 66 ASEFFPHVVDVTHHE 14 77 THHEDALTKTNIIFV 14 85KTNIIFVAIHREHYT 14 89 IFVATHREHYTSLWD 14 113 LIDVSNNMRINQYPE 14 189PIDLGSLSSAREIEN 14 198 AREIENLPLRLFTLW 14 203 NLPLRLFTLWRGPVV 14 212WRGPVVVAISLATFF 14 233 RDVIHPYARNQQSDF 14 261 IVAITLLSLVYLAGL 14 319YSLCLPMRRSERYLF 14 348 SWNEEEVWRIEMYIS 14 373 LLAVTSIPSVSNALN 14 381SVSNALNWREFSFIQ 14 407 TFHVLIYGWKRAFEE 14 409 HVLIYGWKRAFEEEY 14 430PNFVLALVLPSIVIL 14 435 ALVLPSIVILDLLQL 14 30 KVTVGVIGSGDFAKS 13 33VGVIGSGDFAKSLTI 13 101 LWDLRHLLVGKILID 13 139 DSLIVKGFNVVSAWA 13 146FNVVSAWALQLGPKD 13 178 VIELARQLNFIPIDL 13 185 LNFIPIDLGSLSSAR 13 206LRLFTLWRGPVVVAI 13 208 LFTLWRGPVVVAISL 13 223 ATFFFLYSFVRDVIH 13 252IEIVNKTLPIVAITL 13 256 NKTLPIVAITLLSLV 13 280 YQLYYGTKYRRFPPW 13 311FFAMVHVAYSLCLPM 13 358 EMYISFGIMSLGLLS 13 364 GIMSLGLLSLLAVTS 13 376VTSIPSVSNALNWRE 13 391 FSFIQSTLGYVALLI 13 431 NFVLALVLPSIVILD 13

TABLE XLIX V2-HLA-DRB1-1101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 5; each start position is specified, the length of peptide is15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 17 FTPFSCLSLPSSWDY 223 SPGLQALSLSLSSGF 19 28 SWDYRCPPPCPADFF 16 24 SLPSSWDYRCPPPCP 14 5GLQALSLSLSSGFTP 12 8 ALSLSLSSGFTPFSC 12 10 SLSLSSGFTPFSCLS 12 14SSGFTPFSCLSLPSS 12 26 PSSWDYRCPPPCPAD 10

TABLE XLIX V5A-HLA-DRB1-1101-15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 13 LFTFWRGPVVVAISL 1710 PLRIFTFWRGPVVVA 15 15 TFWRGPVVVAISLAT 15 3 AREIENLPLRLFTFW 14 8NLPLRLFTFWRGPVV 14 11 LRLFTFWRGPVVVAI 13 14 FTFWRGPVVVAISLA 12 16FWRGPVVVAISLATF 9 4 REIENLPLRLFTFWR 8

TABLE XLIX V5B-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 11; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 7 WREFSFIQIFCSFAD 22 9EFSFIQIFCSFADTQ 22 16 FCSFADTQTELELEF 11 4 ALNWREFSFIQIFCS 10 13IQIFCSFADTQTELE 10

TABLE XLIX V6-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 13; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 8 LPSIVILGKIILFLP 2118 ILFLPCISRKLKRIK 21 25 SRKLKRIKKGWEKSQ 20 43 EGIGGTIPHVSPERV 20 11IVILGKIILFLPCIS 19 21 LPCISRKLKRIKKGW 16 22 PCISRKLKRIKKGWE 15 5ALVLPSIVILGKIIL 14 46 GGTIPHVSPERVTVM 14 1 NFVLALVLPSIVILG 13 4LALVLPSIVILGKII 13 14 LGKIILFLPCISRKL 13 35 WEKSQFLEEGIGGTI 13 39QFLEEGIGGTIPHVS 13 42 EEGIGGTIPHVSPER 13 15 GKIILFLPCISRKLK 12 17IILFLPCISRKLKRI 12 32 KKGWEKSQFLEEGIG 10 37 KSQFLEEGIGGTIPH 10

TABLE XLIX V7A-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 1 SISMMGSPKSLSETF 21 8PKSLSETFLPNGING 12 12 SETFLPNGINGIKDA 10

TABLE XLIX V7B-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 4 RYLFLNMAYQQSTLG 2214 QSTLGYVALLISTFH 19 2 SERYLFLNMAYQQST 16 7 FLNMAYQQSTLGYVA 13 9NMAYQQSTLGYVALL 10

TABLE XLIX V7C-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 15; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 137 WEFLLRLLKSQAASG 26134 GPLWEFLLRLLKSQA 25 44 PIEWQQDRKIPPLST 24 121 SWRNPVLPHTNGVGP 21 13DLSVEVLASPAAAWK 19 50 DRKIPPLSTPPPPAM 18 62 PAMWTEEAGATAEAQ 18 138EFLLRLLKSQAASGT 18 23 AAAWKCLGANILRGG 17 168 SGTWMKLETIILSKL 17 179LSKLTQEQKSKHCMF 17 157 FTSWSLGEFLGSGTW 16 9 IVILDLSVEVLASPA 15 11ILDLSVEVLASPAAA 15 19 LASPAAAWKCLGANI 15 35 RGGLSEIVLPIEWQQ 15 43LPIEWQQDRKIPPLS 15 73 AEAQESGIRNKSSSS 15 3 ALVLPSIVILDLSVE 14 27KCLGANILRGGLSEI 14 75 AQESGIRNKSSSSSQ 14 89 QIPVVGVVTEDDEAQ 14 135PLWEFLLRLLKSQAA 14 173 KLETIILSKLTQEQK 14 4 LVLPSIVILDLSVEV 13 6LPSIVILDLSVEVLA 13 8 SIVILDLSVEVLASP 13 26 WKCLGANILRGGLSE 13 28CLGANILRGGLSEIV 13 87 SSQIPVVGVVTEDDE 13 90 IPVVGVVTEDDEAQD 13 123RNPVLPHTNGVGPLW 13 130 TNGVGPLWEFLLRLL 13 152 TLSLAFTSWSLGEFL 13 156AFTSWSLGEFLGSGT 13 169 GTWMKLETIILSKLT 13 171 WMKLETIILSKLTQE 13 10VILDLSVEVLASPAA 12 12 LDLSVEVLASPAAAW 12 39 SEIVLPIEWQQDRKI 12 58TPPPPAMWTEEAGAT 12 74 EAQESGIRNKSSSSS 12 77 ESGIRNKSSSSSQIP 12 100DEAQDSIDPPESPDR 12 110 ESPDRALKAANSWRN 12 119 ANSWRNPVLPHTNGV 12 124NPVLPHTNGVGPLWE 12 140 LLRLLKSQAASGTLS 12 150 SGTLSLAFTSWSLGE 12 154SLAFTSWSLGEFLGS 12 176 TIILSKLTQEQKSKH 12

TABLE XLIX V8-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 17; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 13 EGMGGTIPHVSPERV 209 QFLEEGMGGTIPHVS 13 12 EEGMGGTIPHVSPER 13 5 WEKSQFLEEGMGGTI 12 2KKGWEKSQFLEEGMG 10 7 KSQFLEEGMGGTIPH 10

TABLE XLIX V13-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 27; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 1 SISMMGSPKSLSETF 21 8PKSLSETFLPNGING 12 12 SETFLPNGINGIKDA 10

TABLE XLIX V14-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 29; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 12 LFTFWRGPVVVAISL 179 PLRLFTFWRGPVVVA 15 14 TFWRGPVVVAISLAT 15 2 AREIENLPLRLFTFW 14 7NLPLRLFTFWRGPVV 14 10 LRLFTFWRGPVVVAI 13 13 FTFWRGPVVVAISLA 12 15FWRGPVVVAISLATF 9 3 REIENLPLRLFTFWR 8

TABLE XLIX V21-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 43; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 6 LSKLTQEQKTKHCMF 17 3TIILSKLTQEQKTKH 12 8 KLTQEQKTKHCMFSL 8 9 LTQEQKTKHCMFSLI 8

TABLE XLIX V25-HLA-DRB1-1101- 15mers-98P4B6 Each peptide is a portion ofSEQ ID NO: 51; each start position is specified, the length of peptideis 15 amino acids, and the end position for each peptide is the startposition plus fourteen. Pos 123456789012345 score 14 SQKLKRIKKGWEKSQ 2010 LPCISQKLKRIKKGW 16 11 PCISQKLKRIKKGWE 15 3 LGKIILFLPCISQKL 13 7ILFLPCISQKLKRIK 13 4 GKIILFLPCISQKLK 12 6 IILFLPCISQKLKRI 11 8LFLPCISQKLKRIKK 9

TABLE L Properties of 98P4B6 Bioinformatic V.1 Program Outcome ORF ORFfinder Protein length 454 aa Transmembrane region TM Pred 6TM, aa214-232, 261-286, 304-325, 359-379, 393-415, 426-447, N-term insideHMMTop 6TM, aa 215-232 261-279 306-325 360-379 396-415 428- 447 N-termou Sosui 6TM, aa 206-228, 255-277, 304-325, 359-381, 393-415, 428- 450TMHMM 6TM, aa 210-232, 262-284, 304-323, 360-382, 392-414, 427- 449Signal Peptide Signal P none pI pI/MW tool pI 8.74 Molecular weightpI/MW tool 52.0 kD Localization PSORT Plasma membrane 60%, golgi 40%PSORT II Endoplasmic reticulum 39%, plasma membrane 34% Motifs Pfam noknown motifs Prints pyridine nucleotide reductase ProDom Dudulin,oxidoreductase Blocks adenosyl-L-homocysteine hydrolase BioinformaticV.2 Program Outcome ORF ORF finder Protein length 45 aa Transmembraneregion TM Pred 1TM, aa 5-23, N-term inside HMMTop no TM Sosui soubleprotein TMHMM no TM Signal Peptide Signal P none pI pI/MW tool pI 4.2Molecular weight pI/MW tool 4.84 kD Localization PSORT Ouside 37%,microbody 32% PSORT II Extracellular 33%, nuclear 33% Motifs Pfam noknown motifs Prints no known motifs Blocks no known motifs BioinformaticV.5 Program Outcome ORF ORF finder Protein length 419 as Transmembraneregion TM Pred 4TM, aa 214-232, 261-286, 304-325, 359-379 N-term insideHMMTop 4TM, aa 215-232, 259-278, 305-324, 360-379 N-term outside Sosui4TM, aa 209-231, 255-277, 304-325, 356-379 TMHMM 4TM, aa 210-232,262-284, 304-323, 360-382 Signal Peptide Signal P none pI pI/MW tool pI8.1 Molecular weight pI/MW tool 47.9 kD Localization PSORT Plasmamembrane 60%, golgi 40% PSORT II Endoplasmic reticulum 44%, plasmamembrane 22% Motifs Pfam no known motifs Prints no known motifs ProDomDudulin, oxidoreductase Blocks no known motifs Bioinformatic V.6 ProgramOutcome ORF ORF finder Protein length 490 aa Transmembrane region TMPred 6TM, aa 214-232, 261-286, 304-325, 359-379, 393-415, 432-455 HMMTop7TM, aa 140-158, 214-232, 259-280, 305-323, 361-383, 396- 413, 432-455,N-term out Sosui 6TM, aa 206-228, 255-277, 304-325, 359-381, 393-415,428- 450 TMHMM 6TM, aa 210-232, 262-284, 304-323, 360-382, 392-414, 427-449 Signal Peptide Signal P none pI pI/MW tool pI 9.2 Molecular weightpI/MW tool 55.9 kD Localization PSORT Plasma membrane 60%, golgi 40%PSORT II Endoplasmic reticulum 39%, plasma membrane 34% Motifs Pfam noknown motifs Prints pyridine nucleotide reductase ProDom Dudulin,oxidoreductase Blocks adenosyl-L-homocysteine hydrolase BioinformaticV.7 Program Outcome ORF ORF finder Protein length 576 aa Transmembraneregion TM Pred 6TM, aa 214-232, 262-280, 306-322, 331-360, 371-393,525-544. N-term out HMMTop 5TM, aa 215-232, 261-279, 306-325, 342-359,378-397 N- term out Sosui 5TM, aa 206-228, 255-277, 304-325, 339-360,380-402 TMHMM 4TM, aa 210-232, 262-284, 304-323, 343-360 Signal PeptideSignal P none pI pI/MW tool pI 8.5 Molecular weight pI/MW tool 64.5 kDLocalization PSORT Plasma membrane 60%, golgi 40% PSORT II Endoplasmicreticulum 44%, plasma membrane 22% Motifs Pfam no known motifs Printspyridine nucleotide reductase ProDom Dudulin, oxidoreductase Blocks Etsdomain, adenosyl-L-homocysteine hydrolase

TABLE LI Exon boundaries of transcript 98P4B6 v.1 Exon Number Start EndLength 1 23 321 299 2 322 846 525 3 847 1374 528 4 1375 1539 165 5 15401687 148 6 1688 2453 766

TABLE LII(a) Nucleotide sequence (partial, 5′ open) of transcriptvariant 98P4B6 v.2 (SEQ ID NO: 153) agtggatccc ccgggctgca ggctctctctctctctctct cttccgggtt cacgccattc 60 tcctgcctca gcctcccgag tagctgggactacaggtgcc cgccaccatg cccggctgat 120 ttctttttgt atttttagta cagacggagtttcaccgtgt tagccaggat ggtctcgatc 180 tcctgacctc gtgatccgcc cgccttggcctccaaagtgc tgggattaca ggtgtgagct 240 accgcgcccg gcctattatc ttgtactttctaactgagcc ctctattttc tttattttaa 300 taatatttct ccccacttga gaatcacttgttagttcttg gtaggaattc agttgggcaa 360 tgataacttt tatgggcaaa aacattctattatagtgaac aaatgaaaat aacagcgtat 420 tttcaatatt ttcttattcc ttaaattccactcttttaac actatgctta accacttaat 480 gtgatgaaat attcctaaaa gttaaatgactattaaagca tatattgttg catgtatata 540 ttaagtagcc gatactctaa ataaaaataccactgttaca gataaatggg gcctttaaaa 600 atatgaaaaa caaacttgtg aaaatgtataaaagatgcat ctgttgtttc aaatggcact 660 atcttctttt cagtactaca aaaacagaataattttgaag ttttagaata aatgtaatat 720 atttactata attctaaatg tttaaatgcttttctaaaaa tgcaaaacta tgatgtttag 780 ttgctttatt ttacctctat gtgattatttttcttaattg ttatttttta taatcattat 840 ttttctgaac cattcttctg gcctcagaagtaggactgaa ttctactatt gctaggtgtg 900 agaaagtggt ggtgagaacc ttagagcagtggagatttgc tacctggtct gtgttttgag 960 aagtgcccct tagaaagtta aaagaatgtagaaaagatac tcagtcttaa tcctatgcaa 1020 aaaaaaaatc aagtaattgt tttcctatgaggaaaataac catgagctgt atcatgctac 1080 ttagctttta tgtaaatatt tcttatgtctcctctattaa gagtatttaa aatcatattt 1140 aaatatgaat ctattcatgc taacattatttttcaaaaca tacatggaaa tttagcccag 1200 attgtctaca tataaggttt ttatttgaattgtaaaatat ttaaaagtat gaataaaata 1260 tatttatagg tatttatcag agatgattattttgtgctac atacaggttg gctaatgagc 1320 tctagtgtta aactacctga ttaatttcttataaagcagc ataaccttgg cttgattaag 1380 gaattctact ttcaaaaatt aatctgataatagtaacaag gtatattata ctttcattac 1440 aatcaaatta tagaaattac ttgtgtaaaagggcttcaag aatatatcca atttttaaat 1500 attttaatat atctcctatc tgataacttaattcttctaa attaccactt gccattaagc 1560 tatttcataa taaattctgt acagtttcccccaaaaaaag agatttattt atgaaatatt 1620 taaagtttct aatgtggtat tttaaataaagtatcataaa tgtaataagt aaatatttat 1680 ttaggaatac tgtgaacact gaactaattattcctgtgtc agtctatgaa atccctgttt 1740 tgaaataagt aaacagccta aaatgtgttgaaattatttt gtaaatccat gacttaaaac 1800 aagatacata catagtataa cacacctcacagtgttaaga tttatattgt gaaatgagac 1860 accctacctt caattgttca tcagtgggtaaaacaaattc tgatgtacat tcaggacaaa 1920 tgattagccc taaatgaaac tgtaataatttcagtggaaa ctcaatctgt ttttaccttt 1980 aaacagtgaa ttttacatga atgaatgggttcttcacttt ttttttagta tgagaaaatt 2040 atacagtgct taattttcag agattctttccatatgttac taaaaaatgt tttgttcagc 2100 ctaacatact gagttttttt taactttctaaattattgaa tttccatcat gcattcatcc 2160 aaaattaagg cagactgttt ggattcttccagtggccaga tgagctaaat taaatcacaa 2220 aagcagatgc ttttgtatga tctccaaattgccaacttta aggaaatatt ctcttgaaat 2280 tgtctttaaa gatcttttgc agctttgcagatacccagac tgagctggaa ctggaatttg 2340 tcttcctatt gactctactt ctttaaaagcggctgcccat tacattcctc agctgtcctt 2400 gcagttaggt gtacatgtga ctgagtgttggccagtgaga tgaagtctcc tcaaaggaag 2460 gcagcatgtg tcctttttca tcccttcatcttgctgctgg gattgtggat ataacaggag 2520 ccctggcagc tgtctccaga ggatcaaagccacacccaaa gagtaaggca gattagagac 2580 cagaaagacc ttgactactt ccctacttccactgcttttt cctgcattta agccattgta 2640 aatctgggtg tgttacatga agtgaaaattaattctttct gcccttcagt tctttatcct 2700 gataccattt aacactgtct gaattaactagactgcaata attctttctt ttgaaagctt 2760 ttaaaggata atgtgcaatt cacattaaaattgattttcc attgtcaatt agttatactc 2820 attttcctgc cttgatcttt cattagatattttgtatctg cttggaatat attatcttct 2880 ttttaactgt gtaattggta attactaaaactctgtaatc tccaaaatat tgctatcaaa 2940 ttacacacca tgttttctat cattctcatagatctgcctt ataaacattt aaataaaaag 3000 tactatttaa tgatttaaaa aaaaaaaaaaaaaaaaaaaa a 3041

TABLE LIII(a) Nucleotide sequence alignment of 98P4B6 v.1 (SEQ ID NO:154) and 98P4B6 v.2 (SEQ ID NO: 155) Score = 1429 bits (743), Expect =0.0Identities = 750/751 (99%), Gaps = 1/751 (0%) Strand Plus/Plus

NOTE: THERE WAS A SINGLE NUCLEOTIDE INSERTION OF A SINGLE BASE AT 2620OF V.2.

TABLE LIV(a) Peptide sequences (partial) of protein coded by 98P4B6 v.2(SEQ ID NO: 156) SGSPGLQALS LSLSSGFTPF SCLSLPSSWD YRCPPPCPAD FFLYF 45

TABLE LV(a) Amino acid sequence alignment of 98P4B6 v.1 and 98P4B6 v.2--NO SIGNIFICANT HOMOLOGY--

TABLE LII(b) Nucleotide sequence of transcript variant 98P4B6 v.3 (SEQID NO: 157) ttctgctata gagatggaac agtatatgga aagctcccaa gaaagtgaagagaggaaatt 60 ggaaaattgt gagtggacct tctgatactg ctcctccttg cgtggaaaaggggaaagaac 120 tgcatgcata ttattcagcg tcctatattc aaaggatatt cttggtgatcttggaagtgt 180 ccgtatcatg gaatcaatct ctatgatggg aagccctaag agccttagtgaaacttgttt 240 acctaatggc ataaatggta tcaaagatgc aaggaaggtc actgtaggtgtgattggaag 300 tggagatttt gccaaatcct tgaccattcg acttattaga tgcggctatcatgtggtcat 360 aggaagtaga aatcctaagt ttgcttctga attttttcct catgtggtagatgtcactca 420 tcatgaagat gctctcacaa aaacaaatat aatatttgtt gctatacacagagaacatta 480 tacctccctg tgggacctga gacatctgct tgtgggtaaa atcctgattgatgtgagcaa 540 taacatgagg ataaaccagt acccagaatc caatgctgaa tatttggcttcattattccc 600 agattctttg attgtcaaag gatttaatgt tgtctcagct tgggcacttcagttaggacc 660 taaggatgcc agccggcagg tttatatatg cagcaacaat attcaagcgcgacaacaggt 720 tattgaactt gcccgccagt tgaatttcat tcccattgac ttgggatccttatcatcagc 780 cagagagatt gaaaatttac ccctacgact ctttactctc tggagagggccagtggtggt 840 agctataagc ttggccacat tttttttcct ttattccttt gtcagagatgtgattcatcc 900 atatgctaga aaccaacaga gtgactttta caaaattcct atagagattgtgaataaaac 960 cttacctata gttgccatta ctttgctctc cctagtatac cttgcaggtcttctggcagc 1020 tgcttatcaa ctttattacg gcaccaagta taggagattt ccaccttggttggaaacctg 1080 gttacagtgt agaaaacagc ttggattact aagttttttc ttcgctatggtccatgttgc 1140 ctacagcctc tgcttaccga tgagaaggtc agagagatat ttgtttctcaacatggctta 1200 tcagcaggtt catgcaaata ttgaaaactc ttggaatgag gaagaagtttggagaattga 1260 aatgtatatc tcctttggca taatgagcct tggcttactt tccctcctggcagtcacttc 1320 tatcccttca gtgagcaatg ctttaaactg gagagaattc agttttattcagtctacact 1380 tggatatgtc gctctgctca taagtacttt ccatgtttta atttatggatggaaacgagc 1440 ttttgaggaa gagtactaca gattttatac accaccaaac tttgttcttgctcttgtttt 1500 gccctcaatt gtaattctgg atcttttgca gctttgcaga tacccagactgagctggaac 1560 tggaatttgt cttcctattg actctacttc tttaaaagcg gctgcccattacattcctca 1620 gctgtccttg cagttaggtg tacatgtgac tgagtgttgg ccagtgagatgaagtctcct 1680 caaaggaagg cagcatgtgt cctttttcat cccttcatct tgctgctgggattgtggata 1740 taacaggagc cctggcagct gtctccagag gatcaaagcc acacccaaagagtaaggcag 1800 attagagacc agaaagacct tgactacttc cctacttcca ctgctttttcctgcatttaa 1860 gccattgtaa atctgggtgt gttacatgaa gtgaaaatta attctttctgcccttcagtt 1920 ctttatcctg ataccattta acactgtctg aattaactag actgcaataattctttcttt 1980 tgaaagcttt taaaggataa tgtgcaattc acattaaaat tgattttccattgtcaatta 2040 gttatactca ttttcctgcc ttgatctttc attagatatt ttgtatctgcttggaatata 2100 ttatcttctt tttaactgtg taattggtaa ttactaaaac tctgtaatctccaaaatatt 2160 gctatcaaat tacacaccat gttttctatc attctcatag atctgccttataaacattta 2220 aataaaaagt actatttaat gatttaactt ctgttttgaa aaaaaaaaaaaaaaaaaaaa 2280

TABLE LIII(b) Nucleotide sequence alignment of 98P4B6 v.1 (SEQ ID NO:158) and 98P4B6 v.3 (SEQ ID NO: 159) Score = 4013 bits (2087), Expect =0.0Identities = 2116/2128 (99%), Gaps = 1/2128 (0%) Strand = Plus/Plus

NOTE: AN INSERTION OF A SINGLE BASE AT 1845 OF V.3

TABLE LV(b) Peptide sequences of protein coded by 98P4B6 v.3 (SEQ ID NO:160) MESISMMGSP KSLSETCLPN GINGIKDARK VTVGVIGSGD FAKSLTIRLI RCGYHVVIGS60 RNPKFASEFF PHVVDVTHHE DALTKTNIIF VAIHREHYTS LWDLRHLLVG KILIDVSNNM 120RINQYPESNA EYLASLFPDS LIVKGFNVVS AWALQLGPKD ASRQVYICSN NIQARQQVIE 180LARQLNFIPI DLGSLSSARE IENLPLRLFT LWRGPVVVAI SLATFFFLYS FVRDVIHPYA 240RNQQSDFYKI PIEIVNKTLP IVAITLLSLV YLAGLLAAAY QLYYGTKYRR FPPWLETWLQ 300CRKQLGLLSF FFAMVHVAYS LCLPMRRSER YLFLNMAYQQ VHANIENSWN EEEVWRIEMY 360ISFGIMSLGL LSLLAVTSIP SVSNALNWRE FSFIQSTLGY VALLISTFHV LIYGWKRAFE 420EEYYRFYTPP NFVLALVLPS IVILDLLQLC RYPD 454

TABLE LV(b) Amino acid sequence alignment of 98P4B6 v.1 (SEQ ID NO: 161)and 98P4B6 v.3 (SEQ ID NO: 162) Score = 910 bits (2351), Expect= 0.0Identities = 454/454 (100%), Positives = 454/454 (100%) V.1: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS V.3: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60 V.1: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM V.3: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120 V.1:121 RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE V.3: 121RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180 V.1:181 LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA V.3: 181LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240 V.1:241 RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ V.3: 241RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300 V.1:301 CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY V.3: 301CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360 V.1:361 ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE V.3: 361ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420 V.1:421 EEYYRFYTPPNFVLALVLPSIVILDLLQLCRYPD 454EEYYRFYTPPNFVLALVLPSIVILDLLQLCRYPD V.3: 421EEYYRFYTPPNFVLALVLPSIVILDLLQLCRYPD 454

TABLE LII(c) Nucleotide sequence of transcript variant 98P4B6 v.4 (SEQID NO: 163) cccacgcgtc cgcggacgcg tgggcggacg cgtgggttcc tcgggccctcggcgccacaa 60 gctgtccggg cacgcagccc ctagcggcgc gtcgctgcca agccggcctccgcgcgcctc 120 cctccttcct tctcccctgg ctgttcgcga tccagcttgg gtaggcggggaagcagctgg 180 agtgcgaccg ccacggcagc caccctgcaa ccgccagtcg gagagctaagggcaagtcct 240 gaggttgggc ccaggagaaa gaaggcaagg agacattgtc ccaggatattcttggtgatc 300 ttggaagtgt ccgtatcatg gaatcaatct ctatgatggg aagccctaagagccttagtg 360 aaacttgttt acctaatggc ataaatggta tcaaagatgc aaggaaggtcactgtaggtg 420 tgattggaag tggagatttt gccaaatcct tgaccattcg acttattagatgcggctatc 480 atgtggtcat aggaagtaga aatcctaagt ttgcttctga attttttcctcatgtggtag 540 atgtcactca tcatgaagat gctctcacaa aaacaaatat aatatttgttgctatacaca 600 gagaacatta tacctccctg tgggacctga gacatctgct tgtgggtaaaatcctgattg 660 atgtgagcaa taacatgagg ataaaccagt acccagaatc caatgctgaatatttggctt 720 cattattccc agattctttg attgtcaaag gatttaatgt tgtctcagcttgggcacttc 780 agttaggacc taaggatgcc agccggcagg tttatatatg cagcaacaatattcaagcgc 840 gacaacaggt tattgaactt gcccgccagt tgaatttcat tcccattgacttgggatcct 900 tatcatcagc cagagagatt gaaaatttac ccctacgact ctttactctctggagagggc 960 cagtggtggt agctataagc ttggccacat tttttttcct ttattcctttgtcagagatg 1020 tgattcatcc atatgctaga aaccaacaga gtgactttta caaaattcctatagagattg 1080 tgaataaaac cttacctata gttgccatta ctttgctctc cctagtataccttgcaggtc 1140 ttctggcagc tgcttatcaa ctttattacg gcaccaagta taggagatttccaccttggt 1200 tggaaacctg gttacagtgt agaaaacagc ttggattact aagttttttcttcgctatgg 1260 tccatgttgc ctacagcctc tgcttaccga tgagaaggtc agagagatatttgtttctca 1320 acatggctta tcagcaggtt catgcaaata ttgaaaactc ttggaatgaggaagaagttt 1380 ggagaattga aatgtatatc tcctttggca taatgagcct tggcttactttccctcctgg 1440 cagtcacttc tatcccttca gtgagcaatg ctttaaactg gagagaattcagttttattc 1500 agtctacact tggatatgtc gctctgctca taagtacttt ccatgttttaatttatggat 1560 ggaaacgagc ttttgaggaa gagtactaca gattttatac accaccaaactttgttcttg 1620 ctcttgtttt gccctcaatt gtaattctgg atcttttgca gctttgcagatacccagact 1680 gagctggaac tggaatttgt cttcctattg actctacttc tttaaaagcggctgcccatt 1740 acattcctca gctgtccttg cagttaggtg tacatgtgac tgagtgttggccagtgagat 1800 gaagtctcct caaaggaagg cagcatgtgt cctttttcat cccttcatcttgctgctggg 1860 attgtggata taacaggagc cctggcagct gtctccagag gatcaaagccacacccaaag 1920 agtaaggcag attagagacc agaaagacct tgactacttc cctacttccactgcttttcc 1980 tgcatttaag ccattgtaaa tctgggtgtg ttacatgaag tgaaaattaattctttctgc 2040 ccttcagttc tttatcctga taccatttaa cactgtctga attaactagactgcaataat 2100 tctttctttt gaaagctttt aaaggataat gtgcaattca cattaaaattgattttccat 2160 tgtcaattag ttatactcat tttcctgcct tgatctttca ttagatattttgtatctgct 2220 tggaatatat tatcttcttt ttaactgtgt aattggtaat tactaaaactctgtaatctc 2280 caaaatattg ctatcaaatt acacaccatg ttttctatca ttctcatagatctgccttat 2340 aaacatttaa ataaaaagta ctatttaatg attt 2374

TABLE LIII(c) Nucleotide sequence alignment of 98P4B6 v.1 (SEQ ID NO:164) and 98P4B6 v.4 (SEQ ID NO: 165) Score = 404 bits (210), Expect =e−109Identities = 210/210 (100%) Strand = Plus/Plus

Score = 4022 bits (2092), Expect = 0.0Identities = 2092/2092 (100%)Strand = Plus/Plus

TABLE LIV(c) Peptide sequences of protein coded by 98P4B6 v.4 (SEQ IDNO: 166) MESISMMGSP KSLSETCLPN GINGIKDARK VTVGVIGSGD FAKSLTIRLIRCGYNVVIGS 60 RNPKFASEFF PHVVDVTHHE DALTKTNIIF VAIHREHYTS LWDLRHLLVGKILIDVSNNM 120 RINQYPESNA EYLASLFPDS LIVKGFNVVS AWALQLGPKD ASRQVYICSNNIQARQQVIE 180 LARQLNFIPI DLGSLSSARE IENLPLRLFT LWRGPVVVAI SLATFFFLYSFVRDVIHPYA 240 RNQQSDFYKI PIEIVNKTLP IVAITLLSLV YLAGLLAAAY QLYYGTKYRRFPPWLETWLQ 300 CRKQLGLLSF FFAMVHVAYS LCLPMRRSER YLFLNMAYQQ VHANIENSWNEEEVWRIEMY 360 ISFGIMSLGL LSLLAVTSIP SVSNALNWRE FSFIQSTLGY VALLISTFHVLIYGWKRAFE 420 EEYYRFYTPP NFVLALVLPS IVILDLLQLC RYPD 454

TABLE LV(c) Amino acid sequence alignment of 98P4B6 v.1 (SEQ ID NO: 167)and 98P4B6 v.4 (SEQ ID NO: 168) Score = 910 bits (2351), Expect= 0.0Identities = 454/454 (100%), Positives = 454/454 (100%) V.1: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS V.4: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60 V.1: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM V.4: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120 V.1:121 RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE V.4: 121RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180 V.1:181 LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA V.4: 181LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240 V.1:241 RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ V.4: 241RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300 V.1:301 CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY V.4: 301CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360 V.1:361 ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE V.4: 361ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420 V.1:421 EEYYRFYTPPNFVLALVLPSIVILDLLQLCRYPD 454EEYYRFYTPPNFVLALVLPSIVILDLLQLCRYPD V.4: 421EEYYRFYTPPNFVLALVLPSIVILDLLQLCRYPD 454

TABLE LII(d) Nucleotide sequence of transcript variant 98P4B6 v.5 (SEQID NO: 169) cccacgcgtc cgcggacgcg tgggcggacg cgtgggttcc tcgggccctcggcgccacaa 60 gctgtccggg cacgcagccc ctagcggcgc gtcgctgcca agccggcctccgcgcgcctc 120 cctccttcct tctcccctgg ctgttcgcga tccagcttgg gtaggcggggaagcagctgg 180 agtgcgaccg ctacggcagc caccctgcaa ccgccagtcg gagagctaagggcaagtcct 240 gaggttgggc ccaggagaaa gaaggcaagg agacattgtc ccaggatattcttggtgatc 300 ttggaagtgt ccgtatcatg gaatcaatct ctatgatggg aagccctaagagccttagtg 360 aaacttgttt acctaatggc ataaatggta tcaaagatgc aaggaaggtcactgtaggtg 420 tgattggaag tggagatttt gccaaatcct tgaccattcg acttattagatgcggctatc 480 atgtggtcat aggaagtaga aatcctaagt ttgcttctga attttttcctcatgtggtag 540 atgtcactca tcatgaagat gctctcacaa aaacaaatat aatatttgttgctatacaca 600 gagaacatta tacctccctg tgggacctga gacatctgct tgtgggtaaaatcctgattg 660 atgtgagcaa taacatgagg ataaaccagt acccagaatc caatgctgaatatttggctt 720 cattattccc agattctttg attgtcaaag gatttaatgt tgtctcagcttgggcacttc 780 agttaggacc taaggatgcc agccggcagg tttatatatg cagcaacaatattcaagcgc 840 gacaacaggt tattgaactt gcccgccagt tgaatttcat tcccattgacttgggatcct 900 tatcatcagc cagagagatt gaaaatttac ccctacgact ctttactttctggagagggc 960 cagtggtggt agctataagc ttggccacat tttttttcct ttattcctttgtcagagatg 1020 tgattcatcc atatgctaga aaccaacaga gtgactttta caaaattcctatagagattg 1080 tgaataaaac cttacctata gttgccatta ctttgctctc cctagtataccttgcaggtc 1140 ttctggcagc tgcttatcaa ctttattacg gcaccaagta taggagatttccaccttggt 1200 tggaaacctg gttacagtgt agaaaacagc ttggattact aagttttttcttcgctatgg 1260 tccatgttgc ctacagcctc tgcttaccga tgagaaggtc agagagatatttgtttctca 1320 acatggctta tcagcaggtt catgcaaata ttgaaaactc ttggaatgaggaagaagttt 1380 ggagaattga aatgtatatc tcctttggca taatgagcct tggcttactttccctcctgg 1440 cagtcacttc tatcccttcg gtgagcaatg ctttaaactg gagagaattcagttttattc 1500 agatcttttg cagctttgca gatacccaga ctgagctgga actggaatttgtcttcctat 1560 tgactctact tctttaaaag cggctgccca ttacattcct cagctgtccttgcagttagg 1620 tgtacatgtg actgagtgtt ggccagtgag atgaagtctc ctcaaaggaaggcagcatgt 1680 gtcctttttc atcccttcat cttgctgctg ggattgtgga tataacaggagccctggcag 1740 ctgctccaga ggatcaaagc cacacccaaa gagtaaggca gattagagaccagaaagacc 1800 ttgactactt ccctacttcc actgcttttt cctgcattta agccattgtaaatctgggtg 1860 tgttacatga agtgaaaatt aattctttct gcccttcagt tctttatcctgataccattt 1920 aacactgtct gaattaacta gactgcaata attctttctt ttgaaagcttttaaaggata 1980 atgtgcaatt cacattaaaa ttgattttcc attgtcaatt agttatactcattttcctgc 2040 cttgatcttt cattagatat tttgtatctg cttggaatat attatcttctttttaactgt 2100 gtaattggta attactaaaa ctctgtaatc tccaaaatat tgctatcaaattacacacca 2160 tgttttctat cattctcata gatctgcctt ataaacattt aaataaaaagtactatttac 2220 caaaaaaaaa aaaaaaaaaa aaaaaaaaa 2249

TABLE LIII(d) Nucleotide sequence alignment of 98P4B6 v.1 (SEQ ID NO:170) and 98P4B6 v.5 (SEQ ID NO: 171) Score = 398 bits (207), Expect =e−107Identities = 209/210 (99%) Strand = Plus/Plus

Score = 2334 bits (1214), Expect = 0.0Identities = 1218/1220 (99%)Strand = Plus/Plus

Score = 1375 bits (715), Expect = 0.0Identities = 741/749 (98%), Gaps =2/749 (0%) Strand = Plus/Plus

NOTE: A SNP AT 192 AND AT 1510, A DELETION AT 1742-1743, AND ANINSERTION OF SINGLE BASE AT 1830 OF V.5.

TABLE LIV(d) Peptide sequences of protein coded by 98P4B6 v.5 (SEQ IDNO: 172) MESISMMGSP KSLSETCLPN GINGIKDARK VTVGVIGSGD FAKSLTIRLIRCGYHVVIGS 60 RNPKFASEFF PHVVDVTHHE DALTKTNIIF VAIHREHYTS LWDLRHLLVGKILIDVSNNM 120 RINQYPESNA EYLASLFPDS LIVKGFNVVS AWALQLGPKD ASRQVYICSNNIQARQQVIE 180 LARQLNFIPI DLGSLSSARE IENLPLRLFT FWRGPVVVAI SLATFFFLYSFVRDVIHPYA 240 RNQQSDFYKI PIEIVNKTLP IVAITLLSLV YLAGLLAAAY QLYYGTKYRRFPPWLETWLQ 300 CRKQLGLLSF FFAMVHVAYS LCLPMRRSER YLFLNMAYQQ VHANIENSWNEEEVWRIEMY 360 ISFGIMSLGL LSLLAVTSIP SVSNALNWRE FSFIQIFCSF ADTQTELELEFVFLLTLLL 419

TABLE LV(d) Amino acid sequence alignment of 98P4B6 v.1 (SEQ ID NO: 173)and 98P4B6 v.5 (SEQ ID NO: 174) Score = 788 bits (2036), Expect= 0.0Identities = 394/395 (99%), Positives = 394/395 (99%) V.1: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS V.5: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60 V.1: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM V.5: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120 V.1:121 RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE V.5: 121RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180 V.1:181 LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240LARQLNFIPIDLGSLSSAREIENLPLRLFT WRGPVVVAISLATFFFLYSFVRDVIHPYA V.5: 181LARQLNFIPIDLGSLSSAREIENLPLRLFTFWRGPVVVAISLATFFFLYSFVRDVIHPYA 240 V.1:241 RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ V.5: 241RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300 V.1:301 CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY V.5: 301CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360 V.1:361 ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQ 395ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQ V.5: 361ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQ 395 NOTE: A SNP CAUSED A SINGLEAMINO ACID DIFFERENCE AT 211.

TABLE LII(e) Nucleotide sequence of transcript variant 98P4B6 v.6 (SEQID NO: 175) cccacgcgtc cgcggacgcg tgggcggacg cgtgggttcc tcgggccctcggcgccacaa 60 gctgtccggg cacgcagccc ctagcggcgc gtcgctgcca agccggcctccgcgcgcctc 120 cctccttcct tctcccctgg ctgttcgcga tccagcttgg gtaggcggggaagcagctgg 180 agtgcgaccg ccacggcagc caccctgcaa ccgccagtcg gagagctaagggcaagtcct 240 gaggttgggc ccaggagaaa gaaggcaagg agacattgtc ccaggatattcttggtgatc 300 ttggaagtgt ccgtatcatg gaatcaatct ctatgatggg aagccctaagagccttagtg 360 aaacttgttt acctaatggc ataaatggta tcaaagatgc aaggaaggtcactgtaggtg 420 tgattggaag tggagatttt gccaaatcct tgaccattcg acttattagatgcggctatc 480 atgtggtcat aggaagtaga aatcctaagt ttgcttctga attttttcctcatgtggtag 540 atgtcactca tcatgaagat gctctcacaa aaacaaatat aatatttgttgctatacaca 600 gagaacatta tacctccctg tgggacctga gacatctgct tgtgggtaaaatcctgattg 660 atgtgagcaa taacatgagg ataaaccagt acccagaatc caatgctgaatatttggctt 720 cattattccc agattctttg attgtcaaag gatttaatgt tgtctcagcttgggcacttc 780 agttaggacc taaggatgcc agccggcagg tttatatatg cagcaacaatattcaagcgc 840 gacaacaggt tattgaactt gcccgccagt tgaatttcat tcccattgacttgggatcct 900 tatcatcagc cagagagatt gaaaatttac ccctacgact ctttactctctggagagggc 960 cagtggtggt agctataagc ttggccacat tttttttcct ttattcctttgtcagagatg 1020 tgattcatcc atatgctaga aaccaacaga gtgactttta caaaattcctatagagattg 1080 tgaataaaac cttacctata gttgccatta ctttgctctc cctagtataccttgcaggtc 1140 ttctggcagc tgcttatcaa ctttattacg gcaccaagta taggagatttccaccttggt 1200 tggaaacctg gttacagtgt agaaaacagc ttggattact aagttttttcttcgctatgg 1260 tccatgttgc ctacagcctc tgcttaccga tgagaaggtc agagagatatttgtttctca 1320 acatggctta tcagcaggtt catgcaaata ttgaaaactc ttggaatgaggaagaagttt 1380 ggagaattga aatgtatatc tcctttggca taatgagcct tggcttactttccctcctgg 1440 cagtcacttc tatcccttca gtgagcaatg ctttaaactg gagagaattcagttttattc 1500 agtctacact tggatatgtc gctctgctca taagtacttt ccatgttttaatttatggat 1560 ggaaacgagc ttttgaggaa gagtactaca gattttatac accaccaaactttgttcttg 1620 ctcttgtttt gccctcaatt gtaattctgg gtaagattat tttattccttccatgtataa 1680 gccgaaagct aaaacgaatt aaaaaaggct gggaaaagag ccaatttctggaagaaggta 1740 ttggaggaac aattcctcat gtctccccgg agagggtcac agtaatgtgatgataaatgg 1800 tgttcacagc tgccatataa agttctactc atgccattat ttttatgacttctacgttca 1860 gttacaagta tgctgtcaaa ttatcgtggg ttgaaacttg ttaaatgagatttcaactga 1920 cttagtgata gagttttctt caagttaatt ttcacaaatg tcatgtttgccaatatgaat 1980 ttttctagtc aacatattat tgtaatttag gtatgttttg ttttgttttgcacaactgta 2040 accctgttgt tactttatat ttcataatca gacaaaaata cttacagttaataatataga 2100 tataatgtta aaaacaattt gcaaaccagc agaattttaa gcttttaaaataattcaatg 2160 gatatacatt tttttctgaa gattaagatt ttaattattc aacttaaaaagtagaaatgc 2220 attattatac atttttttaa gaaaggacac gttatgttag catctaggtaaggctgcatg 2280 atagcattcc tatatttctc tcataaaata ggatttgaag gatgaaattaattgtatgaa 2340 gcaatgtgat tatatgaaga gacacaaatt aaaaagacaa attaaacctgaaattatatt 2400 taaaatatat ttgagacatg aaatacatac tgataataca tacctcatgaaagattttat 2460 tctttattgt gttacagagc agtttcattt tcatattaat atactgatcaggaagaggat 2520 tcagtaacat ttggcttcca aaactgctat ctctaatacg gtaccaatcctaggaactgt 2580 atactagttc ctacttagaa caaaagtatc aagtttgcac acaagtaatctgccagctga 2640 cctttgtcgc accttaacca gtcaccactt gctatggtat aggattatactgatgttctt 2700 tgagggattc tgatgtgcta ggcatggttc taagtacttt acttgtattatcccatttaa 2760 tacttagaac aaccccgtga gataagtagt tattatcctc attttacacatgagggaccg 2820 aaggatagaa aagttatttt tcaaaggtct tgcagttaat aaatggcagagtgagcattc 2880 aagtccaggt agtcatattc cagaggccac ggttttaacc actaggctctagagctcccg 2940 ccgcgcccct atgcattatg ttcacaatgc caatctagat gcttcctcttttgtataaag 3000 tcactgacat tctttagagt gggttgggtg catccaaaaa tgtataaaaatattattata 3060 ataaacttat tactgcttgt agggtaattc acagttactt accctattcttgcttggaac 3120 atgagcctgg agacccatgg cagtccatat gcctccctat gcagtgaagggccctagcag 3180 tgttaacaaa ttgctgagat cccacggagt ctttcaaaaa tctctgtagagttagtcttc 3240 tccttttctc ttcctgagaa gttctcctgc ctgcataacc attcattagggagtacttta 3300 caagcatgaa ggatattagg gtaagtggct aattataaat ctactctagagacatataat 3360 catacagatt attcataaaa tttttcagtg ctgtccttcc acatttaattgcattttgct 3420 caaactgtag aatgccctac attcccccca ccccaatttg ctatttccttattaaaatag 3480 aaaattatag gcaagataca attatatgcg ttcctcttcc tgaaattataacatttctaa 3540 acttacccac gtagggacta ctgaatccaa ctgccaacaa taaaaagacttttatttagt 3600 agaggctacc tttcccccca gtgactcttt ttctacaact gccttgtcagtttggtaatt 3660 cacttatgat tttctaatgt tctcttggtg aattttatta tcttggaccctctttttttt 3720 tttttttaaa gacagagtct tgctctgtca ccca 3754

TABLE LIII(e) Nucleotide sequence alignment of 98P4B6 v.1 (SEQ ID NO:176) and 98P4B6 v.6 (SEQ ID NO: 177) Score = 404 bits (210), Expect =e−109Identities = 210/210 (100%) Strand Plus/Plus

Score = 2630 bits (1368), Expect = 0.0Identities = 1368/1368 (100%)Strand = Plus/Plus

TABLE LIV(e) Peptide sequences of protein coded by 98P4B6 v.6 (SEQ IDNO: 178) MESISMMGSP KSLSETCLPN GINGIKDARK VTVGVIGSGD FAKSLTIRLIRCGYHVVIGS 60 RNPKFASEFF PHVVDVTHHE DALTKTNIIF VAIHREHYTS LWDLRHLLVGKILIDVSNNM 120 RINQYPESNA EYLASLFPDS LIVKGFNVVS AWALQLGPKD ASRQVYICSNNIQARQQVIE 180 LARQLNFIPI DLGSLSSARE IENLPLRLFT LWRGPVVVAI SLATFFFLYSFVRDVIHPYA 240 RNQQSDFYKI PIEIVNKTLP IVAITLLSLV YLAGLLAAAY QLYYGTKYRRFPPWLETWLQ 300 CRKQLGLLSF FFAMVHVAYS LCLPMRRSER YLFLNMAYQQ VHANIENSWNEEEVWRIEMY 360 ISFGIMSLGL LSLLAVTSIP SVSNALNWRE FSFIQSTLGY VALLISTFHVLIYGWKRAFE 420 EEYYRFYTPP NFVLALVLPS IVILGKIILF LPCISRKLKR IKKGWEKSQFLEEGIGGTIP 480 HVSPERVTVM 490

TABLE LV(e) Amino acid sequence alignment of 98P4B6 v.1 (SEQ ID NO: 179)and 98P4B6 v.6 (SEQ ID NO: 180) Score = 888 bits (2294), Expect= 0.0Identities = 444/444 (100%), Positives = 444/444 (100%) V.1: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS V.6: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60 V.1: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM V.6: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120 V.1:121 RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE V.6: 121RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180 V.1:181 LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA V.6: 181LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240 V.1:241 RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ V.6: 241RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300 V.1:301 CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY V.6: 301CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360 V.1:361 ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE V.6: 361ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420 V.1:421 EEYYRFYTPPNFVLALVLPSIVIL 444 EEYYRFYTPPNFVLALVLPSIVIL V.6: 421EEYYRFYTPPNFVLALVLPSIVIL 444

TABLE LII(f) Nucleotide sequence of transcript variant 98P4B6 v.7 (SEQID NO: 181) ggagaaaatt tacagaaacc cagagccaaa ggtgctctca ggggatcccctgaaacattc 60 aaagccattg cggccccaga agcttgggta ggcggggaag cagctggagtgcgaccgccg 120 cggcagccac cctgcaaccg ccagtcggag gtgcagtccg taggccctggcccccgggtg 180 ggcccttggg gagtcggcgc cgctcccggg gagctgcaag gctcgcccctgcccggcgtg 240 gagggcgcgg ggggcgcgga ggatattctt ggtgatcttg gaagtgtccgtatcatggaa 300 tcaatctcta tgatgggaag ccctaagagc cttagtgaaa cttttttacctaatggcata 360 aatggtatca aagatgcaag gaaggtcact gtaggtgtga ttggaagtggagattttgcc 420 aaatccttga ccattcgact tattagatgc ggctatcatg tggtcataggaagtagaaat 480 cctaagtttg cttctgaatt ttttcctcat gtggtagatg tcactcatcatgaagatgct 540 ctcacaaaaa caaatataat atttgttgct atacacagag aacattatacctccctgtgg 600 gacctgagac atctgcttgt gggtaaaatc ctgattgatg tgagcaataacatgaggata 660 aaccagtacc cagaatccaa tgctgaatat ttggcttcat tattcccagattctttgatt 720 gtcaaaggat ttaatgttgt ctcagcttgg gcacttcagt taggacctaaggatgccagc 780 cggcaggttt atatatgcag caacaatatt caagcgcgac aacaggttattgaacttgcc 840 cgccagttga atttcattcc cattgacttg ggatccttat catcagccagagagattgaa 900 aatttacccc tacgactctt tactctctgg agagggccag tggtggtagctataagcttg 960 gccacatttt ttttccttta ttcctttgtc agagatgtga ttcatccatatgctagaaac 1020 caacagagtg acttttacaa aattcctata gagattgtga ataaaaccttacctatagtt 1080 gccattactt tgctctccct agtatacctc gcaggtcttc tggcagctgcttatcaactt 1140 tattacggca ccaagtatag gagatttcca ccttggttgg aaacctggttacagtgtaga 1200 aaacagcttg gattactaag ttttttcttc gctatggtcc atgttgcctacagcctctgc 1260 ttaccgatga gaaggtcaga gagatatttg tttctcaaca tggcttatcagcagtctaca 1320 cttggatatg tcgctctgct cataagtact ttccatgttt taatttatggatggaaacga 1380 gcttttgagg aagagtacta cagattttat acaccaccaa actttgttcttgctcttgtt 1440 ttgccctcaa ttgtaattct ggatctgtct gtggaggttc tggcttccccagctgctgcc 1500 tggaaatgct taggtgctaa tatcctgaga ggaggattgt cagagatagtactccccata 1560 gagtggcagc aggacaggaa gatcccccca ctctccaccc cgccgccaccggccatgtgg 1620 acagaggaag ccggggcgac cgccgaggcc caggaatccg gcatcaggaacaagtctagc 1680 agttccagtc aaatcccggt ggttggggtg gtgacggagg acgatgaggcgcaggattcc 1740 attgatcccc cagagagccc tgatcgtgcc ttaaaagccg cgaattcctggaggaaccct 1800 gtcctgcctc acactaatgg tgtggggcca ctgtgggaat tcctgttgaggcttctcaaa 1860 tctcaggctg cgtcaggaac cctgtctctt gcgttcacat cctggagccttggagagttc 1920 cttgggagtg ggacatggat gaagctggaa accataattc tcagcaaactaacacaggaa 1980 cagaaatcca aacactgcat gttctcactg ataagtggga gttgaacaatgagaacacat 2040 ggacacaggg aggggaacgt cacacaccag ggcctgtcgg gggtgggaggcctagcaatt 2100 cattagaatt acctgtgaag cttttaaaat gtaaggtttg gatggaatgctcagacccta 2160 ccttagaccc aattaagccc acagctttga gg 2192

TABLE LIII(f) Nucleotide sequence alignment of 98P4B6 v.1 (SEQ ID NO:182) and 98P4B6 v.7 (SEQ ID NO: 183) Score = 2350 bits (1222), Expect =0.0Identities = 1230/1234 (99%) Strand = Plus/Plus

Score = 298 bits (155), Expect = 2e−77Identities = 155/155 (100%) Strand= Plus/Plus

TABLE LIV(f) Peptide sequences of protein coded by 98P4B6 v.7 (SEQ IDNO: 184) MESISMMGSP KSLSETFLPN GINGIKDARK VTVGVIGSGD FAKSLTIRLIRCGYHVVIGS 60 RNPKFASEFF PHVVDVTHHE DALTKTNIIF VAIHREHYTS LWDLRHLLVGKILIDVSNNM 120 RINQYPESNA EYLASLFPDS LIVKGFNVVS AWALQLGPKD ASRQVYICSNNIQARQQVIE 180 LARQLNFIPI DLGSLSSARE IENLPLRLFT LWRGPVVVAI SLATFFFLYSFVRDVIHPYA 240 RNQQSDFYKI PIEIVNKTLP IVAITLLSLV YLAGLLAAAY QLYYGTKYRRFPPWLETWLQ 300 CRKQLGLLSF FFAMVHVAYS LCLPMRRSER YLFLNMAYQQ STLGYVALLISTFHVLIYGW 360 KRAFEEEYYR FYTPPNFVLA LVLPSIVILD LSVEVLASPA AAWKCLGANILRGGLSEIVL 420 PIEWQQDRKI PPLSTPPPPA MWTEEAGATA EAQESGIRNK SSSSSQIPVVGVVTEDDEAQ 480 DSIDPPESPD RALKAANSWR NPVLPHTNGV GPLWEFLLRL LKSQAASGTLSLAFTSWSLG 540 EFLGSGTWMK LETIILSKLT QEQKSKHCMF SLISGS 576

TABLE LV(f) Amino acid sequence alignment of 98P4B6 v.1 (SEQ ID NO: 185)and 98P4B6 v.7 (SEQ ID NO: 186) Score = 753 bits (1944), Expect= 0.0Identities = 390/446 (87%), Positives = 390/446 (87%), Gaps= 55/446 (12%) V.1: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60MESISMMGSPKSLSET LPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS V.7: 1MESISMMGSPKSLSETFLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60 V.1: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM V.7: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120 V.1:121 RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE V.7: 121RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180 V.1:181 LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA V.7: 181LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240 V.1:241 RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ V.7: 241RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300 V.1:301 CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQ V.7: 301CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQ-------------------- 340 V.1:361 ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420                                   STLGYVALLISTFHVLIYGWKRAFE V.7: 341-----------------------------------STLGYVALLISTFHVLIYGWKRAFE 365 V.1:421 EEYYRFYTPPNFVLALVLPSIVILDL 446 EEYYRFYTPPNFVLALVLPSIVILDL V.7: 366EEYYRFYTPPNFVLALVLPSIVILDL 391

TABLE LII(g) Nucleotide sequence of transcript variant 98P4B6 v.8 (SEQID NO: 187) gccccctccg agctccccga ctcctccccg cgctccacgg ctcttcccgactccagtcag 60 cgttcctcgg gccctcggcg ccacaagctg tccgggcacg cagcccctagcggcgcgtcg 120 ctgccaagcc ggcctccgcg cgcctccctc cttccttctc ccctggctgttcgcgatcca 180 gcttgggtag gcggggaagc agctggagtg cgaccgccac ggcagccaccctgcaaccgc 240 cagtcggagg tgcagtccgt aggccctggc ccccgggtgg gcccttggggagtcggcgcc 300 gctcccgagg agctgcaagg ctcgcccctg cccggcgtgg agggcgcggggggcgcggag 360 gatattcttg gtgatcttgg aagtgtccgt atcatggaat caatctctatgatgggaagc 420 cctaagagcc ttagtgaaac ttgtttacct aatggcataa atggtatcaaagatgcaagg 480 aaggtcactg taggtgtgat tggaagtgga gattttgcca aatccttgaccattcgactt 540 attagatgcg gctatcatgt ggtcatagga agtagaaatc ctaagtttgcttctgaattt 600 tttcctcatg tggtagatgt cactcatcat gaagatgctc tcacaaaaacaaatataata 660 tttgttgcta tacacagaga acattatacc tccctgtggg acctgagacatctgcttgtg 720 ggtaaaatcc tgattgatgt gagcaataac atgaggataa accagtacccagaatccaat 780 gctgaatatt tggcttcatt attcccagat tctttgattg tcaaaggatttaatgttgtc 840 tcagcttggg cacttcagtt aggacctaag gatgccagcc ggcaggtttatatatgcagc 900 aacaatattc aagcgcgaca acaggttatt gaacttgccc gccagttgaatttcattccc 960 attgacttgg gatccttatc atcagccaga gagattgaaa atttacccctacgactcttt 1020 actctctgga gagggccagt ggtggtagct ataagcttgg ccacattttttttcctttat 1080 tcctttgtca gagatgtgat tcatccatat gctagaaacc aacagagtgacttttacaaa 1140 attcctatag agattgtgaa taaaacctta cctatagttg ccattactttgctctcccta 1200 gtataccttg caggtcttct ggcagctgct tatcaacttt attacggcaccaagtatagg 1260 agatttccac cttggttgga aacctggtta cagtgtagaa aacagcttggattactaagt 1320 tttttcttcg ctatggtcca tgttgcctac agcctctgct taccgatgagaaggtcagag 1380 agatatttgt ttctcaacat ggcttatcag caggttcatg caaatattgaaaactcttgg 1440 aatgaggaag aagtttggag aattgaaatg tatatctcct ttggcataatgagccttggc 1500 ttactttccc tcctggcagt cacttctatc ccttcagtga gcaatgctttaaactggaga 1560 gaattcagtt ttattcagtc tacacttgga tatgtcgctc tgctcataagtactttccat 1620 gttttaattt atggatggaa acgagctttt gaggaagagt actacagattttatacacca 1680 ccaaactttg ttcttgctct tgttttgccc tcaattgtaa ttctgggtaagattatttta 1740 ttccttccat gtataagccg aaagctaaaa cgaattaaaa aaggctgggaaaagagccaa 1800 tttctggaag aaggtatggg aggaacaatt cctcatgtct ccccggagagggtcacagta 1860 atgtgatgac aaatggtgtt cacagctgcc atataaagtt ctactcatgccattattttt 1920 atgacttcta cgttcagtta caagtatgct gtcaaattat cgtgggttgaaacttgttaa 1980 atgagatttc aactgactta gtgatagagt tttcttcaag ttaattttcacaaatgtcat 2040 gtttgccaat atgaattttt ctagtcaaca tattattgta atttaggtatgttttgtttt 2100 gttttgcaca actgtaaccc tgttgttact ttatatttca taatcaggcaaaaatactta 2160 cagttaataa tatagatata atgttaaaaa caatttgcaa accagcagaattttaagctt 2220 ttaaaataat tcaatggata tacatttttt tctgaagatt aagattttaattattcaact 2280 taaaaagtag aaatgcatta ttatacattt ttttaagaaa ggacacgttatgttagcatc 2340 taggtaaggc tgcatgatag cattcctata tttctctcat aaaataggatttgaaggatg 2400 aaattaattg tatgaagcaa tgtgattata tgaagagaca caaattaaaaagacaaatta 2460 aacctgaaat tatatttaaa atatatttga gacatgaaat acatactgataatacatacc 2520 tcatgaaaga ttttattctt tattgtgtta cagagcagtt tcattttcatattaatatac 2580 tgatcaggaa gaggattcag taacatttgg cttccaaaac tgctatctctaatacggtac 2640 caatcctagg aactgtatac tagttcctac ttagaacaaa agtatcaagtttgcacacaa 2700 gtaatctgcc agctgacctt tgtcgcacct taaccagtca ccacttgctatggtatagga 2760 ttatactgat gttctttgag ggattctgat gtgctaggca tggttctaagtactttactt 2820 gtattatccc atttaatact tagaacaacc ccgtgagata agtagttattatcctcattt 2880 tacacatgag ggaccgaagg atagaaaagt tatttttcaa aggtcttgcagttaataaat 2940 ggcagagtga gcattcaagt ccaggtagtc atattccaga ggccacggttttaaccacta 3000 ggctctagag ctcccgccgc gcccctatgc attatgttca caatgccaatctagatgctt 3060 cctcttttgt ataaagtcac tgacattctt tagagtgggt tgggtgcatccaaaaatgta 3120 taaaaatatt attataataa acttattact gcttgtaggg taattcacagttacttaccc 3180 tattcttgct tggaacatga gcctggagac ccatggcagt ccatatgcctccctatgcag 3240 tgaagggccc tagcagtgtt aacaaattgc tgagatccca cggagtctttcaaaaatctc 3300 tgtagagtta gtcttctcct tttctcttcc tgagaagttc tcctgcctgcataaccattc 3360 attagggagt actttacaag catgaaggat attagggtaa gtggctaattataaatctac 3420 tctagagaca tataatcata cagattattc ataaaatttt tcagtgctgtccttccacat 3480 ttaattgcat tttgctcaaa ctgtagaatg ccctacattc cccccaccccaatttgctat 3540 ttccttatta aaatagaaaa ttataggcaa gatacaatta tatgcgttcctcttcctgaa 3600 attataacat ttctaaactt acccacgtag gtactactga atccaactgccaacaataaa 3660 aagactttta tttagtagag gctacctttc ccaccagtga ctctttttctacaactgcct 3720 tgtcagtttg gtaattcact tatgattttc taatgttctc ttggtgaattttattatctt 3780 gtaccctctt tttttttttt ttttttttta aagacagagt cttgctctgtcacccaggct 3840 ggagtgcagt ggcacgatct cggctcactg caagctctgc ctcccgggttcacgccattc 3900 tcctgcctca gcctcccgag tagctgggac tacaggtgcc cgccaccatgcccggctgat 3960 ttctttttgt atttttagta gagacggagt ttcaccgtgt tagccaggatggtctcgatc 4020 tcctgacctc gtgatccgcc cgccttggcc tccaaagtgc tgggattacaggtgtgagct 4080 accgcgcccg gcctattatc ttgtactttc taactgagcc ctctattttctttattttaa 4140 taatatttct ccccacttga gaatcacttg ttagttcttg gtaggaattcagttgggcaa 4200 tgataacttt tatgggcaaa aacattctat tatagtgaac taatgaaaataacagcgtat 4260 tttcaatatt ttcttattcc ttaaattcca ctcttttaac actatgcttaaccacttaat 4320 gtgatgaaat attcctaaaa gttaaatgac tattaaagca tatattgttgcatgtatata 4380 ttaagtagcc gatactctaa ataaaaatac cactgttaca gataaatggggcctttaaaa 4440 atatgaaaaa caaacttgtg aaaatgtata aaagatgcat ctgttgtttcaaatggcact 4500 atcttctttt cagtactaca aaaacagaat aattttgaag ttttagaataaatgtaatat 4560 atttactata attctaaatg tttaaatgct tttctaaaaa tgcaaaactatgatgtttag 4620 ttgctttatt ttacctctat gtgattattt ttcttaattg ttattttttataatcattat 4680 ttttctgaac cattcttctg gcctcagaag taggactgaa ttctactattgctaggtgtg 4740 agaaagtggt ggtgagaacc ttagagcagt ggagatttgc tacctggtctgtgttttgag 4800 aagtgcccct tagaaagtta aaagaatgta gaaaagatac tcagtcttaatcctatgcaa 4860 aaaaaaaaat caagtaattg ttttcctatg aggaaaataa ccatgagctgtatcatgcta 4920 cttagctttt atgtaaatat ttcttatgtc tcctctatta agagtatttaaaatcatatt 4980 taaatatgaa tctattcatg ctaacattat ttttcaaaac atacatggaaatttagccca 5040 gattgtctac atataaggtt tttatttgaa ttgtaaaata tttaaaagtatgaataaaat 5100 atatttatag gtatttatca gagatgatta ttttgtgcta catacaggttggctaatgag 5160 ctctagtgtt aaactacctg attaatttct tataaagcag cataaccttggcttgattaa 5220 ggaattctac tttcaaaaat taatctgata atagtaacaa ggtatattatactttcatta 5280 caatcaaatt atagaaatta cttgtgtaaa agggcttcaa gaatatatccaatttttaaa 5340 tattttaata tatctcctat ctgataactt aattcttcta aattaccacttgccattaag 5400 ctatttcata ataaattctg tacagtttcc ccccaaaaaa gagatttatttatgaaatat 5460 ttaaagtttc taatgtggta ttttaaataa agtatcataa atgtaataagtaaatattta 5520 tttaggaata ctgtgaacac tgaactaatt attcctgtgt cagtctatgaaatccctgtt 5580 ttgaaatacg taaacagcct aaaatgtgtt gaaattattt tgtaaatccatgacttaaaa 5640 caagatacat acatagtata acacacctca cagtgttaag atttatattgtgaaatgaga 5700 caccctacct tcaattgttc atcagtgggt aaaacaaatt ctgatgtacattcaggacaa 5760 atgattagcc ctaaatgaaa ctgtaataat ttcagtggaa actcaatctgtttttacctt 5820 taaacagtga attttacatg aatgaatggg ttcttcactt tttttttagtatgagaaaat 5880 tatacagtgc ttaattttca gagattcttt ccatatgtta ctaaaaaatgttttgttcag 5940 cctaacatac tgagtttttt ttaactttct aaattattga atttccatcatgcattcatc 6000 caaaattaag gcagactgtt tggattcttc cagtggccag atgagctaaattaaatcaca 6060 aaagcagatg cttttgtatg atctccaaat tgccaacttt aaggaaatattctcttgaaa 6120 ttgtctttaa agatcttttg cagctttgca gatacccaga ctgagctggaactggaattt 6180 gtcttcctat tgactctact tctttaaaag cggctgccca ttacattcctcagctgtcct 6240 tgcagttagg tgtacatgtg actgagtgtt ggccagtgag atgaagtctcctcaaaggaa 6300 ggcagcatgt gtcctttttc atcccttcat cttgctgctg ggattgtggatataacagga 6360 gccctggcag ctgtctccag aggatcaaag ccacacccaa agagtaaggcagattagaga 6420 ccagaaagac cttgactact tccctacttc cactgctttt tcctgcatttaagccattgt 6480 aaatctgggt gtgttacatg aagtgaaaat taattctttc tgcccttcagttctttatcc 6540 tgataccatt taacactgtc tgaattaact agactgcaat aattctttcttttgaaagct 6600 tttaaaggat aatgtgcaat tcacattaaa attgattttc cattgtcaattagttatact 6660 cattttcctg ccttgatctt tcattagata ttttgtatct gcttggaatatattatcttc 6720 tttttaactg tgtaattggt aattactaaa actctgtaat ctccaaaatattgctatcaa 6780 attacacacc atgttttcta tcattctcat agatctgcct tataaacatttaaataaaaa 6840 gtactattta atgattt 6857

TABLE LIII(g) Nucleotide sequence alignment of 98P4B6 v.1 (SEQ ID NO:188) and 98P4B6 v.8 (SEQ ID NO: 189) Score = 3201 bits (1665), Expect =0.0Identities = 1665/1665 (100%) Strand Plus/Plus

Score = 1381 bits (718), Expect = 0.0Identities = 725/726 (99%), Gaps =1/726 (0%) Strand = Plus/Plus

TABLE LIV(g) Peptide sequences of protein coded by 98P4B6 v.8 (SEQ IDNO: 190) MESISMMGSP KSLSETCLPN GINGIKDARK VTVGVIGSGD FAKSLTIRLIRCGYHVVIGS 60 RNPKFASEFF PHVVDVTHHE DALTKTNIIF VAIHREHYTS LWDLRHLLVGKILIDVSNNM 120 RINQYPESNA EYLASLFPDS LIVKGFNVVS AWALQLGPKD ASRQVYICSNNIQARQQVIE 180 LARQLNFIPI DLGSLSSARE IENLPLRLFT LWRGPVVVAI SLATFFFLYSFVRDVIHPYA 240 RNQQSDFYKI PIEIVNKTLP IVAITLLSLV YLAGLLAAAY QLYYGTKYRRFPPWLETWLQ 300 CRKQLGLLSF FFAMVHVAYS LCLPMRRSER YLFLNMAYQQ VHANIENSWNEEEVWRIEMY 360 ISFGIMSLGL LSLLAVTSIP SVSNALNWRE FSFIQSTLGY VALLISTFHVLIYGWKRAFE 420 EEYYRFYTPP NFVLALVLPS IVILGKIILF LPCISRKLKR IKKGWEKSQFLEEGMGGTIP 480 HVSPERVTVM 490

TABLE LV(g) Amino acid sequence alignment of 98P4B6 v.1 (SEQ ID NO: 191)and 98P4B6 v.8 (SEQ ID NO: 192) Score = 888 bits (2294), Expect= 0.0Identities = 444/444 (100%), Positives = 444/444 (100%) V.1: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS V.8: 1MESISMMGSPKSLSETCLPNGINGIKDARKVTVGVIGSGDFAKSLTIRLIRCGYHVVIGS 60 V.1: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM V.8: 61RNPKFASEFFPHVVDVTHHEDALTKTNIIFVAIHREHYTSLWDLRHLLVGKILIDVSNNM 120 V.1:121 RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE V.8: 121RINQYPESNAEYLASLFPDSLIVKGFNVVSAWALQLGPKDASRQVYICSNNIQARQQVIE 180 V.1:181 LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA V.8: 181LARQLNFIPIDLGSLSSAREIENLPLRLFTLWRGPVVVAISLATFFFLYSFVRDVIHPYA 240 V.1:241 RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ V.8: 241RNQQSDFYKIPIEIVNKTLPIVAITLLSLVYLAGLLAAAYQLYYGTKYRRFPPWLETWLQ 300 V.1:301 CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY V.8: 301CRKQLGLLSFFFAMVHVAYSLCLPMRRSERYLFLNMAYQQVHANIENSWNEEEVWRIEMY 360 V.1:361 ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE V.8: 361ISFGIMSLGLLSLLAVTSIPSVSNALNWREFSFIQSTLGYVALLISTFHVLIYGWKRAFE 420 V.1:421 EEYYRFYTPPNFVLALVLPSIVIL 444 EEYYRFYTPPNFVLALVLPSIVIL V.8: 421EEYYRFYTPPNFVLALVLPSIVIL 444

1. A composition comprising an isolated polynucleotide that encodes anantibody or fragment thereof which immunospecifically binds to a proteinhaving the amino acid sequence of SEQ ID NO:3.
 2. A composition of claim1, further comprising a physiologically acceptable carrier.
 3. Apharmaceutical composition that comprises the composition of claim 1 ina human unit dose form.
 4. A composition of claim 1, wherein theantibody is a monoclonal antibody.
 5. A composition of claim 1, whereinthe antibody is a humanized antibody.
 6. A composition of claim 1,wherein the antibody is a human antibody.